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(11) | EP 2 324 886 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | Novel deuterated analogues of tadalafil |
| (57) The present invention relates to derivatives of tadalafil, substituted with deuterium
on the methylene carbon atom situated between the oxygens of the benzodioxol ring,
and optionally further substituted with deuterium atoms in place of normally abundant
hydrogen, and 13C in place of normally abundant 12C. These compounds are selective PDE5 inhibitors and possess advantageous biopharmaceutical
and pharmacokinetic properties. The invention further provides compositions comprising
these compounds and methods of treating diseases and conditions that are responsive
to PDE5 inhibition, alone and in combination with additional agents.
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Technical Field of the Invention
[0001] The present invention relates to derivatives novel isotopologues of tadalafil, (also referred to herein as "Compound 1"), substituted with fluorine and/or deuterium on the methylene carbon atom situated between the oxygens of the berzodioxol ring, optionally further substituted with deuterium atoms in place of normally abundant hydrogen, and 13C in place of normally abundant 12C. The compounds of this invention are selective inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE5) and possess unique biopharmaceutical and pharmacokinetic properties compared to tadalafil. The invention further provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by PDE5 inhibition, particularly those relating to sexual dysfunction. The invention also provides methods for the use of a deuterium- or 13C -containing compound of this invention to determine concentrations of Compound 1, particularly in biological fluids, and to determine metabolism patterns of Compound 1.
Background of the Invention
[0002] Compounds of Formula I have been disclosed as potent and medically useful inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE5). Daugan AC-M, United States Patent 5,859,006 to ICOS; Daugan AC-M and Gellibert F, United States Patent 6,143,746 to ICOS:
(Formula I); or salts of solvates thereof in which: R0 represents hydrogen, halogen or C1-6 alkyl; R1 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloC1-6 alkyl, C3-8cycloalkyl, C3-8cycloalkyl, C1-3alkyl, ary1C1-3alkyl, wherein aryl is phenyl or phenyl substituted with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, methylenedioxy, and mixtures thereof, or heteroaryl C1-3aikyl, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, and mixtures thereof; R2 represents an optionally substituted mono-cyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring
attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulfur, and nitrogen; and R3 represents hydrogen or C1-3 alkyl, or R1 or R3 together represents a 3- or 4- membered alkyl or alkenyl chain component of a 5- or 6-membered ring.
[0003] Compound 1, chemically described variously as pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-; as (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione; and as (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;
(Compound 1) comprises a particularly important example of this genus.
[0004] Compound 1 and pharmaceutical compositions comprising it have utility both alone and, for certain conditions, in combination with additional agents, for the treatment of: erectile dysfunction, stable, unstable and variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular diseases, vascular disorders, thrombocythemia, inflammatory diseases, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, gut motility disorders, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, and irritable bowel syndrome, in humans and in animals; erectile dysfunction in male humans and animals; and female arousal disorder in females. Daugan AC-M and Gellibert F, United States Patent 6,143,746 to ICOS; Daugan AC-M, United States Patent 6,140,329 to ICOS; Daugan AC-M, United States Patent 5,859,006 to ICOS; Anderson NR and Gullapalli RP, United States Patent 6,841,167 to Lilly Icos; Allemeier LL et. al., United States Patent 6,613,768 to Lilly Icos.
[0005] Definitions and descriptions of these conditions are known to the skilled practitioner and are further delineated, for instance, in the above patents and references contained therein; Harrison's Principles of Internal Medicine 16th Edition, Kasper DL et. al. Eds., 2004, McGraw-Hill Professional; and Robbins & Cotran Pathologic Basis of Disease, Kumar V et. al. Eds., 2004, W.B. Saunders. Compound 1 is currently indicated for the treatment of erectile dysfunction. United States Food and Drug Administration (FDA) New Drug Application (NDA) no. 021368; see label approved on 03/31/2005; http://www.fda.gov/cder/foi/label/2005/021368s004,0051b1.pdf.
[0006] The combination of Compound 1 with additional agents extends or enhances its utility in the treatment of sexual deficient states in humans, including those with epilepsy, craniopharyngioma, hypogonadism, or who have had a hysterectomyoophorectomy, hysterectomy or oophorectomy; and to the induction of mating in non-human animals. McCall RB and Meglasson MD, United States Patent 6,903,127 to Pharmacia & Upjohn; McCall RB and Meglasson MD, United States Patent 6,890,945 to Pharmacia & Upjohn; McCall RB and Meglasson MD, United States Patent 6,809,112 to Phannacia & Upjohn. See also Shapira N, US Patent Application 20040009957; Adams MA et. al. US Patent Application 20040063719, Queen's University at Kingston and Callegy Pharmaceuticals Applicants; Fox DNA and Hughes B, US Patent Applications 20040077624 and 20040132731; Hepworth D, US Patent Application 20040180958, Pfizer Applicant; Kalvinish I et. al. US Patent Application 20040242590; US Patent Applications 20030225060, 20040097546, 20040204398, and 20040266821, Merck Applicant; Thomas TN, US Patent Application 20050009835; Bictash MN et. al., US Patent Application 20050049255, Pfizer Applicant; Chiang P et. al. US Patent Applications 20030125334, 20050020604,20050032809, and 20050054656, Pfizer Applicant; Santel DJ, US Patent Application 20050101608; and Ghofrani A, US Patent Application 20050107394.
[0007] Additionally disclosed uses for Compound 1 include methods of treating males with low sperm count to promote fertilization of an ovum; combinations with additional agents to treat hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridemia, diabetes, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, vascular restenosis, and endothelial dysfunction; methods of reducing insulin resistance and preventing ischemia/reperfusion injury; combinations with other agents to treat depression, epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, cyclical oedema, Menires disease, hyperaldosteroneism (primary and secondary), hypercalciuria and lower urinary tract symptoms, other than urinary incontinence, associated with overactive bladder and/or benign prostatic hyperplasia; methods for stimulating ovarian follicular growth, for preventing or treating a condition involving fibrosis, and for alleviating pain or spasticity in a patient suffering from spinal cord injury. Quay SC, World Patent Application WO2004069167, Nastech Applicant; Cohen DS, US Patent Application 20030139429; Lautt WW and Macedo P, US Patent Application 20030181461; Kukreja R, US Patent Application 20040009957; Patrick J and Davis M, US Patent Application 20050143314; Nonaka S and Maruyama T, US Patent Application 20040082653; Rawson DJ, US Patent Application 20040132801, Warner-Lambert Applicant; Dack KN et. al., US Patent Application 20040138274, Warner-Lambert Applicant; Field MJ and Williams RG, US Patent Applications 20040092522 and 20040157847, Warner-Lambert Applicant; Westbrook SL and Zanzinger JF, US Patent Application 20040167095; Taylor CP Jr et. al., US Patent Application 20040180958, Warner-Lambert Applicant; Burgess GM, US Patent Application 20040186046, Pfizer Applicant; Palmer SS et. al. US Patent Application 20040259792; Lautt WW, US Patent Application 20050049293; Gonzalez-Cadavid, NF and Rajfer J, US Patent Application 20050085486; Takasaka S, US Patent Application 20050107405, Warner-Lambert Applicant; and Lautt WW and Macedo P, US Patent Application 20050119272, DiaMedica Applicant.
[0008] Compound 1 has been characterized by in vitro inhibition studies of human cyclic guanosine monophosphate-specific phosphodiesterases and has been demonstrated to have high potency and selectivity for the type 5 isoform over other human phosphodiesterases. In cultured rat aortic smooth muscle cells, Compound 1 dose-dependently increases intracellular concentrations of cGMP. For example, see Porst H, Int. J. Impot. Res. 2002 14(Suppl 1): S57; Daugan A et. al. J. Med. Chem. 2003 46: 4533; Daugan AC-M and Gellibert F, United States Patent 6,143,746 to ICOS. PDE subtype selectivity is believed to be clinically important due to the potential for side effects associated with inhibition of other PDEs. For instance, inhibition of the PDE6 and possibly PDE1 subtypes are believed to cause the flushing, disrupted color vision and headaches clinically associated with less selective inhibitors (see, for instance, BischoffE, Int. J. Impot. Res. 2004 16(Suppl. 1): S11; Kuan J and Brock G, Expert Opin. Investig. Drugs 2002 11: 1605).
[0009] Compound 1 has also been characterized in the spontaneous rat hypertension model as causing significant and long-lived blood pressure reduction following oral dosing. See e.g. Daugan A et. al., J. Med. Chem. 2003 46: 4533.
[0010] In multiple human clinical studies in males with mild to severe erectile dysfunction, treatment with Compound 1 resulted in highly significant patient-reported increases in penetration ability and ability to maintain erection during intercourse versus treatment with placebo. These benefits were observed in a wide cross section of patients including those suffering from spinal cord injuries or diabetes. See, e.g. Giuliano F et. al. Eur. Urol. 2000 37(Suppl. 2): Abst. 320; Bella AJ and Brock GB, Curr. Urol. Rep. 2003 4: 472; Del Popolo G et. al. Spinal Cord. 2004 42: 643; Fonseca V et. al., Diabetologia 2004 47: 1914. Studies comparing patient preferences between Compound 1 and another commercial PDE5 inhibitor have consistently indicated a statistically significant preference for Compound 1, which has been suggested to be due to the longer pharmacological half life of Compound 1 providing a greater window of opportunity for sexual spontaneity. See Doggrell SA, Expert Opin. Pharmacother. 2005 6: 75; Stroberg P et. al., Clin. Ther. 2003 25: 2724; Govier F, Clin. Ther. 2003 25: 2709; Porst H, Int. J. Impot. Res. 2002 14(Suppl. 1): S57,
[0011] Following oral administration to humans, Compound 1 is well absorbed, followed by extensive oxidative and phase II metabolism with only a minor amount of Compound 1 being excreted unchanged (FDA NDA no. 02368, label approved on 03/31/2005). The major metabolic pathway proceeds by initial oxidative cleavage of the benzodioxol ring to forming a catechol metabolite. Subsequent phase II metabolism ensues, including mainly methylation and glucuronidation; see Scheme I. In vitro measurements indicate that these metabolites do not contribute to the clinical activity of Compound 1. When Compound 1 is dosed concurrently with inhibitors of cytochrome 3A4 (CYP3A4), clinically meaningful increases in the half-life and exposure of Compound 1 measured as area under the plasma-time concentration curve (AUC) occur, leading to lower labeled dosing recommendations in patients taking such medications.
[0012] Burgess GM et. al., US Patent Application 20040186046, Pfizer Inc. Applicant ("the '046 application"), discloses PDE5 inhibitors, including Compound 1, and all isotopic variants thereof, as being useful to treat diabetes. The '046 application suggests that substitution of PDE5 inhibitors with isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, The '046 application docs not teach which PDE5 inhibitors, nor what portion of any particular PDE5 inhibitor, should be substituted with isotopes in order to produce greater metabolic stability.
[0013] It is therefore desirable to create a compound displaying the beneficial activities of Compound 1, but with a reduced rate of metabolism to further extend its pharmacological effective life.
Summary of the Invention
[0014] The present invention solves the problems set forth above by providing a compound of Formula II:
or a prodrug or a prodrug salt thereof, or a solvate or polymorph of the foregoing, wherein:
X1 and X2 are simultaneously fluoro; or X1 is deuterium and X2 is selected from hydrogen or deuterium;
each Y is independently selected from deuterium or hydrogen;
the hydrogen attached to the indole nitrogen is optionally replaced by deuterium; and
each carbon is independently optionally replaced by 13C.
[0015] In one embodiment, X1 and X2 are simultaneously hydrogen, producing a compound of Formula IIII:
[0016] In one preferred embodiment of Formula III, the compound has the formula:
(Compound 2), or a prodrug or a prodrug salt thereof, or a solvate, hydrate or polymorph of the foregoing, wherein the naturally abundant hydrogen attached to the indole nitrogen is not replaced by deuterium and wherein no naturally abundant carbon atoms are replaced by 13C.
[0018] In another embodiment, X1 is deuterium and X2 is hydrogen or deuterium, resulting in a compound of the formula:
(IV), or a prodrug or prodrug salt thereof; or a hydrate, solvate or polymorph thereof; wherein:
D is deuterium; Y is deuterium or hydrogen; each hydrogen is optionally and independently replaced with deuterium and each carbon is optionally and independently replaced with 13C.
[0020] Another preferred embodiment is prodrug salt of a compound of formula IV wherein the counterion of the saltable prodrug is pharmaceutically acceptable.
[0021] The compounds of Formulae II, III and IV possess both altered physicochemical properties and great stability to benzodioxol ring cleavage by CYP3A4 due to the presence of fluorine and, in the case of deuterium-containing compounds of Formulae II, III and IV, replacement of hydrogen by deuterium. These novel compounds thus have beneficially enhanced pharmacological effects as compared to Compound 1. Compounds of Formulae II, III and IV, and compositions comprising them, are useful to reduce or ameliorate the severity, duration, or progression, or enhance function compromised by a disorder beneficially treated by inhibiting PDE5, or by increasing intracellular cGMP concentrations. Preferred applications for compounds of Formulae II, III and IV include methods of use in treating sexual disorders, more preferably erectile dysfunction and female arousal disorder; and cardiovascular disorders.
[0022] Fluorination has unpredictable effects on the biological activity of compounds in which it is incorporated in place of hydrogen; see e.g. Smart BE, J. Fluorine Chem. 2001 109: 3 and Ismail FMD, J. Fluorine Chem. 2002 118: 27. This is due to the exceedingly high electronegativity of fluorine relative to hydrogen, and the significantly larger van der Waals volume of fluorine in a C-F bond relative to hydrogen in a C-H bond.
[0023] 2,2-Difluorinated benzodioxols are known and have been incorporated into bioactive agents, but to date are not constituents in any human drugs of which applicant is aware. See for instance Shimizu M and Hiyama T, Angew. Chem. Intl. Ed. 2005 44: 214. Their synthetic manipulation is known (e.g. see Schlosser M et. al. Eur. J. Org. Chem. 2003: 452) but the majority of known 2,2-difluorobenzodioxols possess electron-withdrawing substituents which serve to stabilize the difluoromethylenedioxy ring to hydrolytic cleavage. Indeed, in some cases 2,2-difluorobenzodioxols bearing even mildly electron donating substituents such as alkyl groups are known to resist purification by standard silica gel chromatography due to their extreme instability; see e.g. Kuroboshi M and Hiyama T, Synlett 1994:251.
[0024] Surprisingly, a fluorine-containing compound of Formula II or III is sufficiently stable to allow ready synthetic access. It also beneficially retains high affinity for PDE5, as well as substantial separation of that activity from inhibition of other PDE enzymes, in particular PDE1 and PDE6, and actively increases intracellular cGMP in arterial and corpous cavernosum smooth muscle.
[0025] Incorporation of deuterium in place of hydrogen is known to produce significant effects on the physiological and pharmacological activities of the substituted compound. For instance, N-nitrosamines substituted with deuterium can display increased, decreased, or unchanged carcinogenicity depending on where in the compound hydrogen is replaced with deuterium and on the identity of the compound to which substitutions are made (Lijinsky W et. al. Food Cosmet. Toxicol. 1982 20: 393; Lijinsky W et. at JCNI 1982 69: 1127). Similarly, both increases and decreases in bacterial mutagenicity of deuterium-substituted aza-amino acids are known, depending on the identity of the amino acid derivative and position of substitution (Mangold JB et. at Mutation Res. 1994 308: 33). Reduced hepatotoxicity of certain deuterium-substituted compounds is known (Gordon WP et. al. Drug Metab. Dispos.198715: 589; Thompson DC et. al. Chem. BioI. Interact. 1996 101: 1). Deuterium substitution can affect compound's odors (Turin L, Chem. Senses 1996 21: 773) and plasma protein binding (Echmann ML et. al. J. Pharm. Sci. 1962 51: 66; Cherrah Y. et. al. Biomed. Environm. Mass Spectrom. 1987 14: 653; Cherrah Y. et. al. Biochem. Pharmacol. 1988 37: 1311). Changes in the biodistribution and clearance of certain deuterium-substituted compounds suggests changes in their recognition by active transport mechanisms (Zello GA et. al. Metabolism 1994 43: 487; Gately SJ et. al. J. Null. Med. 1986 27: 388; Wade D, Chem. Biol. Interact. 1999 117:191).
[0026] Replacement of hydrogen with deuterium at sites subject to oxidative metabolism by, for instance, heme proteins such as cytochrome P450 and peroxidase enzymes, is known in certain, but not all, cases to produce a significant reduction in the rate of metabolism due to the primary isotope effect of breaking the C-1H versus C-2H bond (see, e.g., Guengerich FP et. al. J. Biol. Chem. 2002 277: 33711; Kraus, JA and Guengerich, FP, J. Biol. Chem. 2005 280: 19496 ; Mitchell KH et. al., Proc. Natl. Acad. Sci. USA 2003 109: 3784; Nelson SD and Trager WF, Drug Metab. Dispos. 2003 31: 1481; Hall LR and Hanzlik, RP J. Biol. Chem. 1990 265:12349; Okazaki O. and Guengerich FP J. Biol. Chem. 268,1546; Iwamura S et. al. J. Pharmacobio-Dyn. 1987 10: 229). If the C-H bond breaking step is rate-limiting a substantial isotope effect can be observed. If other steps determine the overall rate of reaction, the isotope effect may be insubstantial. In cases where a rate limiting step of a reaction involves rehybridization of the attached carbon from sp2 to sp3, deuterium substitution often creates a negative isotope effect, speeding up the reaction rate. Introducing deuterium into a compound at a site subject to enzymatic oxidation does not predictably produce a significant pharmacokinetic change. See for instance Mamada K et. al. Drug Metab. Dispos. 1986 14: 509; Streeter AJ et. al. Arch. Toxicol. 1990 64: 109; Morgan DS et. al., Int. Arch. Occup. Environ. Health 1993 65(1 Suppl.): S139.
[0027] Although incorporation of deuterium into specific organic compounds can change their pharmacological properties, general exposure to and incorporation of deuterium is safe within levels potentially achieved by use of compounds of this invention as medicaments. For instance, the weight percentage of hydrogen in a mammal (approximately 9%) and natural abundance of deuterium (approximately 0.015%) indicates, for instance, that an average adult US male normally contains approximately 1.2 grams of deuterium (see e.g. Harper VW et. al. "Review of Physiological Chemistry" 16th Edition, 1977, Lange Medical Publications; Ogden CL et. al. CDC Adv. Data 2004 347:1; www.cdc.gov,/nchs/data/ad/ad347.pdf).Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka DM and Finkel AJ, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. N.Y. Acad. Sci 1960 84: 736; Czakja DM et. al., Am. J. Physiol. 1961 201: 357). Higher deuterium concentrations, usually in excess of 20%, can be toxic in animals. However, acute replacement of as high as 15%-23% of the hydrogen in humans' fluids with deuterium was found not to cause toxicity (Blagojevic N et. al. in "Dosimetry & Treatment Planning for Neutron Capture Therapy", ZamenhofR, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison WI pp.125-134.). These authors report a clinical protocol in their practice involving oral administration of up to 1 liter per day of deuterated water (D2O) for up to 5 days, followed by intravenous administration of 4 liters of deuterated water prior to radiation procedures; this deuterated water is readily incorporated throughout the body beyond the fluid compartment, including in glucose and glycogen, fats, and cholesterol and thus cell walls (e.g. see Diabetes Metab. 1997 23: 251). In a 70 kg human male, 15% replacement of the hydrogen in the fluid compartment with deuterium corresponds to incorporation of approximately 1 kg of deuterium or the equivalent of approximately 5 kg of deuterated water. These quantities are orders of magnitude beyond the conceived level of administration of any of the deuterium-containing compounds of this invention.
[0028] Deuterium tracers including deuterium-labeled drugs and doses, in some cases repeatedly, of thousands to tens of thousands of milligrams of deuterated water, are also used in healthy humans of all ages including neonates and pregnant women, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward A et. al., Lancet 1979 7: 13; Schwarcz HP, Control. Clin. Trials 1984 5(4 Suppl): 573; Eckhardt CL et. al. Obes. Res. 2003 11: 1553; Rodewald LE et. al., J. Pediatr. 1989 114: 885; Butte NF et. al. Br. J. Nutr. 1991 65: 3; MacLennan AH et. al., Am. J. Obstet. Gynecol. 1981 139: 948). Thus, it is clear that any deuterium released, for instance, during the metabolism of the deuterium-containing compounds of this invention poses no health risk.
[0029] The compounds of this invention display reduced rates of oxidative metabolism as compared with the medically important Compound 1. This is expected to further extend the pharmacological lifetime of a therapeutic dose of compounds of this invention with respect to a similar dose of Compound 1, beneficially extending the patient's window of opportunity for sexual spontaneity.
[0030] The altered properties of the isotopically modified compounds of this invention will not obliterate their ability to bind to their protein target. This is because such binding is primarily dependent upon non-covalent binding between the protein and the inhibitor which may be impacted both positively and negatively by isotopic substitution, depending on the specific substitution involved, and any negative effects that a heavy atom of this invention may have on the highly optimized non-covalent binding between compounds of formula I and serotonin uptake proteins will be relatively minor. Major factors contributing to the noncovalent recognition of small molecules by proteins and the binding strength between them include: Van der Waals forces, hydrogen bonds, ionic bonds, molecular reorganization, desolation energy of the small molecule, hydrophobic interactions and, in certain instances, displacement energy for pre-existing bound ligands. See, for instance, Goodman & Gilman's The Pharmacological Basis of Therapeutics) Tenth Edition, Hardman JG and Limbird LE, eds. McGraw-Hill, 2001 and The Organic Chemistry of Drug Design and Drug Action, Silverman RB, 2004, Academic Press.
[0031] The compounds of this invention possess molecular topology that is well within the conformational envelope encompassed by the known active compounds of Formula 1. The replacement of hydrogen by deuterium does not alter molecular shape and exchange of 13C for 12C is conformationally neutral (Holtzer ME et. al., Biophys. J. 2001 80: 939). Deuterium replacement does cause a slight decrease in Van der Waals radius (Wade D, Chem. Biol. Interact, 1999 117: 191); but applicant believes that such decrease will not greatly reduce binding affinity between the molecule and its receptor. Furthermore, the smaller size of the deuterated compounds prevents their being involved in new undesirable steric clashes with the binding protein relative to the Compound 1. Neither deuterium nor 13C atoms in the compounds of this invention contribute significantly to hydrogen bonding or ionic interactions with the protein receptors. This is because the major hydrogen bond and ionic interactions formed by Compound 1 with PDE5 are mediated by the nitrogens and oxygens within Compound 1 and possibly its indole NH proton acting as a hydrogen bond donor. Any deuterium atoms attached to the indole nitrogen will be rapidly exchanged with bulk solvent protons under physiological conditions. Protein reorganization or side chain movement will be identical between a compound of this invention and their light atom isotopologues. Desolvation energy of a compound of this invention will be equivalent to or less than that of Compound 1, resulting in neutral or increased binding affinity for the receptor; Turowski M et. al, J. Am. Chem. Soc. 2003 125: 13836. The replacement of 13C in place of 12C in compounds of this invention will have no practical change in desolvation.
Detailed Description Of The Invention
[0032] The present invention provides a compound of Formula II:
(II), wherein:
X1 and X2 are simultaneously fluoro; or X1 is deuterium and X2 is selected from hydrogen or deuterium;
each Y is independently selected from deuterium or hydrogen;
the hydrogen attached to the indole nitrogen is optionally replaced by deuterium; and
each carbon is independently optionally replaced by 13C.
[0033] In one preferred embodiment of Formula II, at least one Y is deuterium. More preferably one or more of Y4, Y7 Y8a, Y8b, Y9a, Y9b or, Y9c are deuterium. Even more preferred embodiments are a compound wherein Y4 is deuterium, a compound wherein Y7 is deuterium, a compound wherein Y8a and Y8b are both deuterium, a compound wherein each of Y9a, Y9b and, Y9c are deuterium; and a compound combining one or more of the foregoing deuterium substitutions.
[0034] In each of the preferred compounds set forth above, it is further preferred that all hydrogen atoms not specifically replaced with deuterium and all carbon atoms not specifically replaced with 13C are present at their natural isotopic abundance. Throughout this specification, reference to "each Y" includes, independently, all "Y" groups including for example Y3, Y4, Y6 ,Y7 , Y8 , Y8a ,Y8b, Y9 Y9a, Y9b, Y9c, Y10, Y11, Y11a Y11b, Y13, Y14, Y15, and Y16, where applicable.
[0035] In one preferred embodiment, the invention provides a compound wherein X1 and X2 are simultaneously fluoro:
(III), or a prodrug or a prodrug salt thereof, or a solvates or polymorph of the foregoing.
[0036] In a preferred embodiment of Formula III, the compound has the formula:
(Compound 2), or a prodrug or a prodrug salt thereof, or a solvate, hydrate or polymorph of the foregoing, wherein the hydrogen attached to the indole nitrogen is not replaced by deuterium and wherein no carbon atoms are replaced by 13C.
[0037] In another preferred embodiment, the invention provides a compound wherein X1 is deuterium and X2 is selected from hydrogen or deuterium:
(IV), or a prodrug or prodrug salt thereof; or a hydrate, solvate or polymorph thereof; wherein: D is deuterium; Y is deuterium or hydrogen; each hydrogen is optionally and independently replaced with deuterium; and each carbon is optionally and independently replaced with 13C.
[0038] According to a preferred embodiment of Formula IV, Y is deuterium. Even more preferred is when up to three additional hydrogen atoms are replaced by deuterium.
[0040] The term "compound" as used herein, is intended to include prodrugs and prodrug salts of a compound of this invention. The term also includes any solvates, hydrates and polymorphs of any of the foregoing. The specific recitation of "prodrug," "prodrug salt," "solvate," "hydrate," or "polymorph" in certain aspects of the invention described in this application shall not be interpreted as an intended omission of these forms in other aspects of the invention where the term "compound" is used without recitation of these other forms,
[0041] As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of the formulae disclosed herein that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of any one of the formulae disclosed herein that comprise -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed); see also Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs".
[0042] As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
[0043] A prodrug salt is a compound formed between an acid and a basic group of the prodrug, such as an amino functional group, or a base and an acidic group of the prodrug, such as a carboxyl functional group. In a preferred embodiment, the prodrug salt is a pharmaceutically acceptable salt. According to another preferred embodiment, the counterion to the saltable prodrug of the compound of formula I is pharmaceutically acceptable. Pharmaceutically acceptable counterions include, for instance, those acids and bases noted herein as being suitable to form pharmaceutically acceptable salts.
[0044] Particularly favored prodrugs and prodrug salts are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species. Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. See, e.g., Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987, 30,451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ.: Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 1975,28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, 1. H. Medicinal Research Reviews 1981, 1, 189-214.
[0045] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
[0046] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucaronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromlc acid, and especially those formed with organic acids such as maleic acid.
[0047] Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups of prodrugs of this invention include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
[0048] As used herein, the term "hydrate" means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
[0049] The term "solvate" means a compound which further includes a stoichiometric or non-stoicbiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
[0050] As used herein, the term "polymorph" means solid crystalline forms of a compound or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat, light or moisture), compressibility and density (important in formulation and product manufacturing), hygroscopicity, solubility, and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.
[0051] The compounds of the present invention contain asymmetric carbon atoms. As such, a compound of this invention can exist as an individual stereoisomer as well as a mixture of stereoisomers. Accordingly, a compound of the present invention will include not only a stereoisomeric mixture, but also individual respective stereoisomers substantially free from other stereoisomers. The term "substantially free" as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, are present. Methods of obtaining or synthesizing stereoisomers are well known in the art and may be applied as practicable to final compounds or to starting material or intermediates. In another embodiment, the compound is an isolated compound.
[0052] The compounds of the invention may be synthesized by well-known techniques. The starting materials and certain intermediates used in the synthesis of the compounds of this invention are available from commercial sources or may themselves be synthesized using reagents and techniques known in the art, including those synthesis schemes delineated herein. See, for instance, Daugan AC-M, US Patent 5,859,006, Assigned to ICOS Corporation; Daugan AC-M, US Patent 6,140,329, Assigned to ICOS Corporation; Daugan AC-M and Gellibert F, US Patent 6,143,746, Assigned to ICOS Corporation; and Daugan AC-M et. al., J. Med. Chem. 2003 46: 4533. Each of these documents is incorporated herein by reference.
[0053] A convenient method for producing compounds of Formula II is shown graphically in scheme II. In Scheme II, E represents a functional group that is known in the art of organic synthesis as an ester group, or functional equivalent, labile to ring closure during the formation of cyclic amides. Suitable E groups include, for instance, methyl, ethyl, propyl, butyl, isobutyl, cyclopropylethyl, phenyl, benzyl, 4-chlorobenzyl, 2-nitrobenzyl, allyl, propargyl, trichloroethyl, and so forth. Many such additional suitable groups will be evident to those of skill in the art; for instance, certain amides can also be in such cyclization reactions. Preferred E groups include methyl, ethyl, benzyl, allyl, and most preferably, methyl. Each Y is independently hydrogen or deuterium. Z represents a leaving group such as are known in the art, many of which will be apparent to the skilled artesian. Preferred Z groups include halides such as chloride, bromide, and iodide; and sulfonates such as tosylate, mesylate, brosylate, nosylate, and the like. Chloride and bromide are more preferred. R represents an acid activating group such as are known in the art, including halide such as fluoride, chloride and bromide; anhydrides such as symmetrical anhydrides, pivalic anhydride, and other mixed anhydrides such as those formed upon reaction with chloroformates; activated esters such as pentafluoromethyl, succinimidyl, and the like. Other hydrogen and carbon atoms in compounds of formulae II, XIII, XIV and XV are optionally replaced with deuterium and 13C, respectively. Modifications of the above scheme will be apparent to those of skill in the art of organic synthesis.
[0054] Deuterated and 13C-substitated indole, D,L-tryptophan, haloacetates such as chloroacetic acid and chloracetyl chloride, and glycine derivatives, are commercially available (e.g. C/D/N Isotopes, Pointe-Claire, Quebec, Canada; Sigma Aldrich (ISOTEC), St. Louis, MO) and allow synthesis of the correspondingly labeled tryptophan derivatives and acetyl-labeled compounds of formula XIV by means known in the art of organic and biochemical synthesis. For instance, see Greenstein JP, Methods Enzymol. 1957 3: 554; Stewart KK and Doherty RF, Proc. Natl. Acad. Sci. USA 1973 70: 2850; Venkatachalam S et. al., Org. Prep. Proc. Intl. 1993 25: 249; Evans DA et. al., in Peptides, Chemistry and Biology, Marshall GR (Ed.) 1999 Escom, Leiden, Holland p. 143; Evans DA et. al., J. Am. Chem. Soc. 1990 112: 4011; Schollkopf U, Pure Appl. Chem. 1983 55: 1799; Myers AG and Gleason JL, Org. Synth. 1999 76: 57; Watanabe T and Snell EE, Proc. Natl. Acad. Sci USA 1972 69: 1086; and Xiong C et. al. J. Org. Chem. 2002 22: 1399.
[0055] Fluorinated compounds of Formula III an be readily synthesized by the skilled chemist. For instance, (3,4-difluoromethylonedioxy)bromobenzene (also known as 5-bromo-2,2-difluorobenzo[d][1,3]dioxole) can be obtained as an item of commerce or prepared as described by Benefiel RL and Krumkalns EV, US Patent 4,110,099 to Eli Lilly, Metal-halogen exchange followed by reaction with a formylating reagent such as, for instance, dimethylformamide yields the compound of Formula III. Heavy atom isotopologues of Formula III are also available by means known in the art of organic synthesis. For instance, reaction of the aforementioned organometallic reagent with commercially available deuterated or 13C formyl-substituted dimethylformamide yields isotopologues bearing heavy atoms at the formyl group. Reaction of 3,4-dihydroxybromobenzene with 13C-labled methylene chloride by means known in the art (e.g. Cabedo N et. al., J. Med. Chem. 2001 44: 1794; Panseri P et. al. US Patent 5,936,103 to Borregaard Italia), followed by conversion of the resulting (3,4-methylene-13C-dioxy)bromobenzene to its difluoromethylene analog (e.g. US Patent 4,110,099) and formylation installs 13C in the methylene carbon of Formula III. Analogous methylene fluorination of the commercial 5,6-dibromobenzo[d][1,3]dioxolc, available e.g. from Chemos GmbH, Regenstauf, Germany as 1,2-dibromo-4,5-methylenedioxy-benzene, followed by reaction with one equivalent of a metallating reagent such as n-butyllithium, and subsequent deuterium quench, yields 5-bromo-6-deutero-2,2-dif!uorobenzo[d][1,3]dioxole. Subsequent metallation and formylation then yields the compound of Formula III wherein Y4 is deuterium. Due to the strong acidic nature of the 2,2-difluorobenzo[d](1,3]dioxole ring ortho to the oxygen atoms, essentially all substitution patterns are accessible through halogenation and lithiation, or catalytic reduction of halogens under deuterium gas by means known in the art (e.g. see Yadav JS et. al., Adv. Synth. Catal. 2004 346: 77; Kirefu T, et. al. J. Label. Compd. Radiopharm. 2001 44: 329) and removable protection as necessary. See Gorecka J et. al. Eur. J. Org. Chem. 2004: 64 ; and Schlosser M et. al., Eur. J. Org. Chem. 2003: 452. 2,2-Difluorobenzo[d][1,3]dioxoles are also available by a different approach involving conversion of the corresponding catechols to thiocarbonates, for instance using thiophosgene, followed by reaction with a fluorinating reagent such as n-Bu4NH2F3 and a suitable oxidant such as N-halo-succinmide or 1,3-dibromo-5,5-dimethylhydantoin (Kuroboshi M and Hiyama T, Synlett 1994 251; Cousseau J and Albert P, Bull. Chim. Soc. Fr. 1986 910).
[0056] 2,2-Dif!uorobenzo[d][1,3]dioxole-5-carboxaldehyde and its heavy atom isotopologues may be used in place of the non-fluorinated, light atom analog (i.e. benzo[d][1,3]dioxole-5-carboxaldehyde) in any of the reaction schemes known for the synthesis of Compound 1 to produce a compound of Formula III. Due to the electron withdrawing nature of the carboxaldehyde substituent, this 1,3-benzodioxole derivative is reasonably stable to acidic conditions, but appropriate care may be helpful, for instance, in acidic condition and reaction workups to avoid any degradation of the reaction product, such as those in Pictet-Spengler reaction, if such an approach is used to produce Compound 2.
[0057] The acid cyclization catalyst can be a strong protic acid (see e.g. Whaley WM and Govindachari TR, Org. React. 1951 6: 74), or a Lewis acid or Bronsted acid-assisted Lewis acid (e.g. Yamada H et. al. J. Org. Chem. 1998 63: 6348). Many variations in this cyclization reaction, commonly referred to as the Pictet-Spengler reaction, are known, including those that enhance enantiomeric or diastereomeric excesses in the products. For instance, see Rozwadowski MD, Heterocycles1994 39: 903; Campiglia P et. al., Mol. Divers. 2004 8:427, Horiguchi Y et. al. Chem. Pharm. Bull. 2003 51: 1368, and Nakamura S et. al., Org. Lett. 2003 5: 2087. If the reaction is carried out in aprotic solvent with a Lewis acid, or alternatively under protic conditions wherein the acid protons have been replaced with deuterium, e.g. using CF3CO2D, then the resulting compound of formula XIV will bear a deuterium at Y7.
[0058] Deuterated compounds of Formula IV can be synthesized, for instance, by reaction of 3,4-dihydroxybenzaldehyde with suitable deuterated methylenation reagents. Examples of such reagents include, for instance, mono and di-deuterated forms of dihalomethanes such as dichloromethane, dibromomethane, bromochloromethane, diiodomethane, and the like. The synthesis ofbenzodioxols from catechol (o-dihydroxyphenyl) precursors is well known in the art and is described, for instance by Cabedo N et. al., J. Med. Chem. 2001 44: 1794; Walz AJ and Sundberg RJ, J. Org. Chem., 2000 65: 8001; Orús L et. al., J. Med. Chem. 2002 45: 4128; Chang J et. al. Helv. Chim. Acta 2003 86:2239; Moreau A et. al., Tetrahedron 2004 60: 6169; and Panseri P et. al. US Patent 5,936,103 to Borregaard Italia, each of which is herein incorporated by reference. The latter reference provides a particularly efficient method which for large-scale production that can be adapted to the readily available dichlorodideuteromethane.
[0059] In Scheme II, separation of the tetrahydro-β-carboline cis-trans isomers; acylation, for instance with chloroacetyl chloride; and ring closure, preferably with methylamine, is then carried out in a manner analogous to that described for the synthesis of Compound 1 in the art, such as in the above-cited references.
[0060] Deuterated, 13C-labeled methylamine is commercially available, allowing isotopic substitution of the N-methyl group attached to the dioxopiperazine ring.
[0061] By means as described above and other that will be apparent to those of skill in the art of organic synthesis, substitution of hydrogens and carbons in compounds of this invention by deuterium and 13C, respectively, may be readily accomplished.
[0062] Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. Reaction optimization and scale-up may advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g. Design And Optimization in Organic Synthesis, 2nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jähnisch, K et al, Angew. Chem. Int. Ed. Engl. 2004 43: 406; and references therein). Additional reaction schemes and protocols may be determined by the skilled artesian by use of commercially available structure-searchable database software, for instance, SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searching using an internet search engine such as Google® or keyword databases such as the US Patent and Trademark Office text database.
[0063] The synthetic methods described herein may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein.
[0064] According to another embodiment, the invention provides any of above-described intermediate compounds XTV or XV, wherein at least one hydrogen or carbon atom has been substituted by deuterium or 13C, respectively. The invention also provides intermediate compound XIII, wherein one X1 is deuterium and X2 is selected from hydrogen or deuterium.
[0065] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable .. intermediate compounds, treating a disease or condition responsive to the reduction of PDE5 activity).
[0066] The term "isotopologue" refers to species that differ from a compound of this invention only in the isotopic composition of their molecules or ions. The terms "lighter isotopologue" and "lighter atom isotopologue" as used herein, refer to species that differs from a compound of this invention in that it comprises one or more light isotopic atoms 1H or 12C at positions occupied by a deuterium or 13C. For the purposes of this invention, 11C is not referred to as a light isotope of carbon.
[0067] A specific compound of this invention may also be referred to as a "heavy atom isotopic compound" to distinguish it from its lighter isotopologues when discussing mixtures ofisotopologues. This is because a specific compound and all of its lighter isotopologues, including Compound 2 which lacks deuterium and 13C, are compounds of Formula II.
[0068] Chemical naming terminology can be complex and different chemical names can often reasonably be applied to the same structure. To avoid any confusion, "Compound 1" refers to the free base form of the active PDE5-inhibing agent of the drug approved for sale in the US by the US FDA in NDA no. 021368.
[0069] It will be recognized that many commonly occurring atoms in biological systems exist naturally as mixtures of isotopes. Thus, any compound of Formula I inherently comprises small amounts of deuterated and/or 13C-containing isotopologues. The present invention differentiates such forms having minor amounts of such isotopologues from its scope in that the term "compound" as used in this invention refers to a composition of matter that is predominantly a specific isotopologue. A compound, as defined herein, in embodiments contains less than 10%, preferably less than 6%, and more preferably less than 3% of all other isotopologues. A compound of this invention preferably comprises hydrogen and carbon atoms, not specifically designated as deuterium and 13C, respectively, in their natural isotopic abundance. Compositions of matter that contain greater than 10% of all other specific isotopologues combined are referred to herein as mixtures and must meet the parameters set forth below. These limits of isotopic composition, and all references to isotopic composition herein, refer solely to the active form of the compound of Formula II and do not include the isotopic composition ofhydrolysable portions of prodrugs, or of prodrug salt counterions, certain of which, such as chloride and bromide, exist naturally as mixtures comprising substantial percentages of multiple isotopes.
[0070] The term "heavy atom" refers to isotopes of higher atomic weight than the predominant naturally occurring isotope.
[0100] The invention further provides compositions comprising (consisting essentially of, consisting of) a mixture of a compound of this invention and its lighter isotopologues. These mixtures may occur, for instance, simply as the result of an inefficiency of incorporating the isotope at a given position; intentional or inadvertent exchange of protons for deuterium, e.g. exchange of bulk solvent for heteroatom-attached deuterium; or intentional mixtures of pure compounds.
[0101] In one embodiment, such mixtures comprise at least about 50% of the heavy atom isotopic compound (i.e., less than about 50% of lighter isotopologues). More preferable is a mixture comprising at least 80% of the heavy atom isotopic compound. Most preferable is a mixture comprising 90% of the heavy atom isotopic compound.
[0102] In an alternate embodiment the mixture comprises a compound and its lighter isotopologues in relative proportions such that at least about 50%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95% and most preferably at least 98% of the compounds in said mixture comprise an isotope at each position containing a stable heavy atom isotope in the full isotopic compound. The following exemplifies this definition. A hypothetical compound of the invention contains deuterium at positions Y9a, Y9b and Y9c. A mixture comprising this compound and all of its potential lighter isotopologues and the relative proportion of each is set forth in the table below.
Table 1.
| Y9a | Y9b | Y9c | Relative Amt | |
| Compound | D | D | D | 40% |
| Isotopologue 1 | D | D | H | 15% |
| Isotopologue 2 | D | H | D | 14% |
| Isotopologue 3 | H | D | D | 13% |
| Isolopologue 4 | D | H | H | 6% |
| Isotopologue 5 | H | D | H | 5% |
| Isotopologue 6 | H | H | D | 4% |
| Isotopologue 7 | H | H | H | 3% |
| % of compounds comprising an isotope at position indicated position | (40%+15%+ 14%+6%)= 75% | (40%+15%+ 13%+5%)= 73% | (40%+14%+ 13%+4%)= 72% |
[0103] From the table it can be seen that the compound plus lighter isotopologues 1, 2 and 4 comprise the isotope deuterium at position Y9a. These compounds are present in the mixture at relevant amounts of 40%, 15%, 14% and 6%. Thus, 75% of the mixture comprises the isotope at Y9a that is present in the compound. The compound plus lighter isotopologues 1, 3 and 5 comprise the isotope deuterium at position Y9b. These compounds are present in the mixture at relevant amounts of 40%, 15%, 13% and 5%. Thus, 73% of the mixture comprises the isotope at Y9b that is present in the compound. The compound plus lighter isotopologues 2, 3 and 6 comprise the isotope deuterium at position Y9c. These compounds are present in the mixture at relevant amounts of 40%, 14%, 13% and 4%. Thus, 71 % of the mixture comprises the isotope at Y9c that is present in the compound. Accordingly, this mixture comprises a compound and its lighter isotopologues in relative proportions such that 71 % of the compounds in said mixture comprise an isotope at each position containing a stable heavy atom isotope in the full isotopic compound.
[0104] The invention also provides compositions comprising an effective amount of a compound of Formula II, or a prodrug, or prodrug salt thereof, or a solvate, hydrate, or polymorph of the foregoing; and an acceptable carrier. Preferably, a composition of this invention is formulated for pharmaceutical use ("a pharmaceutical composition"), wherein the carrier is a pharmaceutically acceptable carrier. The canier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in amounts typically used in medicaments.
[0105] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-Nock polymers, polyethylene glycol and wool fat.
[0106] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. See Doherty PC Jr et. at US Patent 6,548,490 assigned to Vivus, Inc.; Place Via, US Patent 6,469,016 assigned to Vivus, Inc. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed.1985).
[0107] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary shaping the product.
[0108] In certain preferred embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. For instance, see Anderson NR and Gullapalli RP, US Patent 6,841,167 assigned to Lilly Icos.
[0109] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). Such coatings are of particular value in the delivery of a compound of Formula II, and more specifically for delivery of Compound 2.
[0110] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Surfactants such as sodium lauryl sulfate may be useful to enhance dissolution and absorption.
[0111] Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
[0112] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
[0113] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
[0114] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal or vaginal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
[0115] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
[0116] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-knowm in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Such administration is known, to be effective with erectile dysfunction drugs: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
[0117] Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
[0118] Thus, according to another embodiment, the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
[0119] According to another embodiment, the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
[0120] According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers. Implantable mechanical devices are also known; see for instance Gerber MT, US Patent Applications 20950010259,20050033372, 20050070969, assigned to Medtronic Inc.
[0121] According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
[0122] According to another embodiment, the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
[0123] Where an organ or tissue is accessible because of removal from the patient, such organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
[0124] The present invention further provides pharmaceutical compositions comprising an effective amount of one or more compound of the invention in combination with an effective amount of a second therapeutic agent useful for treating or preventing a condition selected from stable angina, unstable angina, variant angina;, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, thrombocythemia, an inflammatory disease, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, a gut motility disorder, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, pretend labor, benign prostatic hypertrophy, or irritable bowel syndrome, in a human or nonhuman animal body; treatment of a sexual deficiency state in a human, including the state of female sexual dysfunction, including recurrent conditions, and treatment of patients who have a co-existing condition of epilepsy, craniopharyngioma, hypogonadism or who has had a hysterectomyoophorectomy, hysterectomy or oophorectomy; as well as hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridemia, diabetes, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, vascular restenosis, endothelial dysfunction, depression, epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, cyclical oedema, Menires disease, hyperaldosteroneism (primary and secondary), hypercalciuria and lower urinary tract symptoms, other than urinary incontinence, associated with overactive bladder and/or benign prostatic hyperplasia; or of inducing mating in a non-human mammal.
[0125] Such second therapeutic agents useful in combination with the compounds of this invention include, but are not limited to: a vasodilator, prostaglandin E1, prostacyclin, an α-adrenergic blocker, a mixed α,β-blocker, an α2-adrenergic blockers, an ACE inhibitor, an NEP inhibitor, a centrally acting dopaminergic agent, a vasoactive intestinal peptide, a calcium channel blocker, a thiazide diuretic, (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one, (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)- thione and pharmaceutically acceptable salts thereof; a 5-HT2 receptor ligand, in particular, 5-HT2a and 5-HT2c. receptor ligands; an acetylcholine esterase antagonist: a vasopressin receptor family antagonist, or a pharmaceutically acceptable derivative thereof; 1-deprenyl or propargylamine compounds; human melanocortin-4 receptor (MC-4R) agonists; gamma-butyrobetaine; an alpha-2-delta ligand; an angiotensin II receptor antagonist; a prostaglandin E2 receptor subtype EP1, antagonist; an endothelin antagonist; an antidiabetic agent, an HMG-Co-a reductase inhibitor, a serotonin reuptake inhibitor (SSRI), or a pharmaceutically acceptable salt thereof; and combinations of the foregoing.
[0126] Examples of vasodilators include, but are not limited to, nitroglycerin, isosorbide dinitrate, pentaerythrityl tetranitrate, isosorbide-5-mononitrate, propatyl nitrate, trolnitrate, nicroandil, mannitol hexanitrate, inositol hexanitrate, N-[3-nitratopivaloyl]-6-eysteine ethyl ester, isoamyl nitrite, S-nitroso-N-acetyl-D,L-penicillamine, 1,2,5-oxadiazole-2-oxide, furazan-N-oxide, molsidomine, mesocarb, an iron nitrosyl compound, sodium nitroprusside, nitric oxide, and mixtures thereof.
[0127] Examples of a-adrenergic blockers include, but are not limited to, phentolamine and prazocin.
[0130] Examples of ACE inhibitors include, but are not limited to, quinapril, enalapril, captopril, spirapril, fosinopril, moexipril, enalaprilat, ramipril perindopril, indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril, delapril, cilazapril and combinations thereof.
[0131] Examples of NEP inhibitors include, but are not limited to, those disclosed by Hepworth D, US Patent Application 20040180941, Pfizer Applicant and Dack KN, US Patent Application 20040138274, Warner-Lambert Applicant.
[0132] Examples of centrally acting dopaminergic agents include, but are not limited to, apomorphine.
[0133] Examples of calcium channel blockers include, but are not limited to, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, and verapamil.
[0134] Examples ofthiazides include, but are not limited to, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlothiazide, trichlormethiazide, polythiazide or benzthiazide.
[0135] Examples of 5-HT2a and 5-HT2c receptor ligands include, but arc not limited to, those disclosed by Chiang P et. al. in US Patent applications 20050054656, 20050020604, and 20050032809, Pfizer Applicant.
[0136] Examples of acetylcholine esterase antagonists include, but are not limited to, donepezil, galanthamine, rivastigme, tacrine, physostigime, neostigmine, edrophonium, pyridostigmine, demecarium, pyridostigmine, phospholine, metrifonate, zanapezil, and ambenonium.
[0137] Examples of vasopressin receptor family antagonists include, but are not limited to, relcovaptan, atosiban, conivaptan, OPC21268, or 8-chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraazo-benzo[e]azulene, or a pharmaceutically acceptable salt or solvate thereof; and those disclosed by Wayman CP and Russell RJ, United States Patent Application 20050014848, Pfizer Applicant.
[0138] Examples of propargylamine compounds include, but are not limited to, those disclosed by Yu PH et. al., US Patent 5,508,311 and in references cited therein.
[0139] Examples of MC-4R agonists include, but are not limited to, those disclosed by Merck, Applicant in US Patent Applications 20030225060,20040097546, 20040204398, and 20040266821.
[0141] Examples of angiotensin II receptor antagonists include, but are not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, ohnesartan medoxomil, saralasin, telmisartan and valsartan and pharmaceutically acceptable salts thereof.
[0142] Examples of prostaglandin E2 receptor subtype EP1 antagonists include, but are not limited to, 4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-5trifluoromethylphen- oxymethyl]benzoic acid; 4-[2--[N-isopropyl-N-(5-methyl-2-furylsulfonyl)-aminol-4,5dimethylphenoxymethyl]benzoic acid; 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5dimethylphenoxymethyl]benzoic acid;4-[6-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5yloxymethyl]cinnamic acid; 3-methyl-4-[6-[-N-isobuiyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5yloxymethyl]cinnamic acid; 4-[4,5-dimethyl-2-[N-methyl-N-(5-methyl-2-furylsulfonyl)-N-propylamino]phenoxymethyl]benzoic acid; 4-[6-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5yloxymethyl]benzoic acid; non-toxic salts thereof, or esters thereof.
[0143] Examples of endothelin antagonists include, but are not limited to, non-peptidal endothelin antagonists such as bosentan, ETA/ETB receptor antagonist such as PD 145065, and endothelin converting enzyme such as phosphoramidon.
[0144] Examples of antidiabetic agents include, but are not limited to, insulin secretion enhancers, insulin sensitivity enhancers, insulin signaling pathway modulators, such as inhibitors of protein tyrosine phosphatases (PTPases), antidiabetic non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT); compounds influencing a dysregulated hepatic glucose production, such as inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase (PDHK) inhibitors; inhibitors of gastric emptying; insulin; inhibitors of GSK-3; retinoid X receptor (RXR) agonists; agonists of β-3 AP; agonists of uncoupling proteins (UCPs); non-glitazone type PPARγ-agonists; dual PPARγ/PPARα agonists; antidiabetic vanadium containing compounds; incretin hormones, such as glucagon-like peptide-1 (GLP-1) and GLP-1 agonists; β-cell imidazoline receptor antagonists; miglitol; and α2-adrenergic antagonists.
[0145] Examples of HMG-Co-A reductase inhibitors include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, pitavastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, mevastatin, and the pharmaceutically acceptable salts, esters, lactones and isomeric forms thereof
[0146] Examples of serotonin uptake inhibitors include, but are not limited to, femoxetine, fluoxetine, fluvoxamine, indalpine, indeloxazine, milnacipran, paroxetine, sertraline, sibutramine, zimeldine, citalopram, escitalopram, fenfluramine, venlafaxine, duloxetine and those disclosed by Marek GJ et. al., United States Patent Application 20050014848, Pfizer Applicant.
[0147] In another embodiment, the invention provides separate dosage forms of a compound of this invention and a second therapeutic agent that are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
[0148] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to reduce or ameliorate the severity, duration or progression, or enhance function compromised by a disorder associated with high PDE5 activity or low intracellular concentrations of cGMP, for instance in arterial walls or in the corpus cavernosal smooth muscle; to prevent the advancement of a disorder associated with low vascular or smooth muscle intracellular concentrations of cGMP, cause the regression of a disorder associated with low vascular or smooth muscle intracellular concentrations of cGMP, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
[0149] In certain preferred embodiments, treatment according to the invention provides a reduction in or prevention of at least one symptom or manifestation of a disorder that has been linked to PDE5 activity, as determined in vivo or in vitro inhibition of at least about 10%, more preferably 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of such activity. With respect to inhibition of PDE5 activity, the term "effective amount" means an amount that results in a detectable reduction in the ability of PDE5 to convert cAMP or cGMP or their 32P-labeled isotopologues to, respectively, 5'-AMP or 5'-GMP or their 32P-labeled isotopologues; or increase in the amount or concentration of intracellular cGMP, particularly in arterial and corpus cavernosal smooth muscle tissue, in a patient or in a biological sample; or the correction of or relief from a behavior, deficit, symptom, syndrome or disease, or enhancement of otherwise compromised function that has been linked to low intracellular cGMP levels, alone or in combination with another agent or agents; or the induction of a behavior, activity or response that has been linked to normalized or increased intracellular cGMP levels.
[0150] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., (1966) Cancer Chemother Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. An effective amount of a compound of this invention can range from about 0.001 mg/kg to about 500 mg/kg, more preferably 0.01 mg/kg to about 50 mg/kg, yet more preferably 0.025 mg/kg to about 1.5 mg/kg. Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
[0151] For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of the second therapeutic agents useful in this invention are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are entirely incorporated herein by reference.
[0152] It is expected that some of the second therapeutic agents listed above will act synergistically with the compounds of this invention. When this occurs, its will allow the effective dosage of the second therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the second therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation.
Methods of Treatment
[0153] In one embodiment, the present invention provides a method of inhibiting PDE5 or increasing intracellular cGMP levels, particularly in arterial and corpus cavernosal smooth muscle, in a subject comprising the step of administering to said subject an effective amount of a compound of Formula II, preferably combined in a composition with a pharmaceutically acceptable carrier.
[0154] Preferably the method is employed to treat a subject suffering from or susceptible to one or more disease or disorder selected from erectile dysfunction, stable, unstable and variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular diseases, vascular disorders, thrombocythemia, inflammatory diseases, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, gut motility disorders, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, and irritable bowel syndrome, in humans and in animals; erectile dysfunction in male humans and animals; and female arousal disorder in females. The method can also be employed to treat a subject suffering from or susceptible to one or more disease or disorder selected from low sperm count in males preventing successful fertilization of an ovum; reducing insulin resistance; preventing ischemia/reperfusion injury; preventing or treating a condition involving fibrosis; and for alleviating pain or spasticity in a patient suffering from spinal cord injury. Other embodiments include any of the methods herein wherein the subject is identified as in need of the indicated treatment.
[0155] Preferably, the method is used to treat a sexual disorder or a cardiovascular disorder, More preferably, the sexual disorder is selected from erectile dysfunction or female arousal disorder. Mosat preferably, the condition to be treated is erectile dysfunction.
[0156] Another aspect of the invention is a compound of Formula II for use in increasing intracellular cGMP levels or inhibiting PDE5. Preferably that use is in the treatment or prevention in a subject of a disease, disorder or symptom set forth above.
[0157] Another aspect of the invention is use of a compound of Formula II in the manufacture of a medicament for increasing intracellular cGMP levels or inhibiting PDE5. Preferably, the medicament is used for treatment or prevention in a subject of a disease, disorder or symptom set forth above.
[0158] In another embodiment, the method of treating one of the diseases, disorders or symptoms set forth above further comprises the step of administering to said patient a second therapeutic agent which alone or in combination with Compound 1 is effective to sexually deficient states in humans with epilepsy, craniopharyngioma, hypogonadism, or who have had a hysterectomyoophorectomy, hysterectomy or oophorectomy; or to induce mating in non-human animals.
[0159] In yet another embodiment, the method of treatment comprises the further step of administering to said patient a second therapeutic agent which alone or in combination with Compound 1 is effective to treat one or more of hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridemia, diabetes, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, vascular restenosis, endothelial dysfunction, depression, epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, cyclical oedema, Menires disease, hyperaldosteroneism (primary and secondary), hypercalciuria and lower urinary tract symptoms, other than urinary incontinence, associated with overactive bladder and/or benign prostatic hyperplasia.
[0160] The second therapeutic agent may be administered together with a compound of Formula II as part of a single dosage form or as multiple dosage forms. Alternatively, the second therapeutic agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administering of the second therapeutic agent may occur before, concurrently with, and/or after the administering of the compound of this invention. When the administration of the second therapeutic agent occurs concurrently with a compound of this invention, the two (or more) agents may be administered in a single dosage form (such as a composition of this invention comprising a compound of the invention and a second therapeutic agent as described above), or in separate dosage forms. The administration of a composition of this invention comprising both a compound of the invention and an additional therapeutic agent to a subject does not preclude the separate administration of said therapeutic agent, any other therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
[0161] Effective amounts of a second therapeutic agent useful in the methods of this invention are well known to those skilled in the art and guidance for dosing may be found in patents referenced herein. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range. In one embodiment of the invention where a second therapeutic agent is administered to an animal, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
[0162] Second therapeutic agents useful in the method of treatment of this invention are the same as those described above as part of combination compositions.
[0163] According to another aspect, the invention provides a compound of Formula II and one or more of the above-described second therapeutic agents, either in a single composition or as separate dosage forms for use in the treatment or prevention in a subject of a disease, disorder or symptom set forth above.
[0164] In yet another aspect, the invention provides the use of a compound of Formula II and one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a subject of a disease, disorder or symptom set forth above.
[0165] The compounds of this invention may be assayed in vitro by known methods. For instance, human PDE5 inhibition assays, and the related phosphodiesterases PDE3, PDE4, and PDE6, are commercially available from MDS Pharma Services. Cerep (Paris, France) provides commercial assays for PDE1, PDE2, PDE3, PDE4, PDE5 and PDE6. Methodology for such assays is also well known; see for instance Komas N et. al., Br. J. Pharmacol 1991 104: 495; Wells IN, Biochim. Biophys. Acta 1975 19: 430; and Rotella DP et. al., J. Med. Chem. 2000 43: 1257. Increases in intracellular levels of cGMP in appropriate tissue is also readily determined; see for instance Daugan AC-M and Gellibert F, United States Patent 6,143,746 to ICOS. Thus, both enzymatic activity and specificity for compounds of this invention, as well as cellular efficacy, are readily determined.
[0166] Animal models measuring antihypertensive activity are also available and provide predictive in vivo measurement of PDE5 inhibitors' ability to effect vasodilatation by increases in arterial smooth muscle cGMP levels as well as the potency and length of action of the inhibitors. See e.g. Daugan AC-M and Gellibert F, United States Patent 6,143,746 to ICOS; Daugan A et. al. J. Med. Chem. 2003 46: 4533. Each of the compounds of this invention may be tested by such means. The compounds of this invention may also be tested by in vitro assays, to quantify their activity, resistance to liver metabolism by cellular or tissue exposure, or by isolated metabolic enzymes such as CYP3A4, or by in vivo pharmacokinetic measurement (available commercially, e.g. from SRI Biosciences, Memo Park, CA; Covance, Princeton NJ; Charles River Laboratories, Wilmington, MA; and Cerep, Seattle WA; among others) and compared to Compound 1.
[0168] According to another embodiment, the invention provides a method of determining the concentration of Compound 1 in a biological sample, said method comprising the steps of:
- a) adding a known concentration of a second compound to said biological sample, said
second compound having the formula: Formula II:
wherein:X1 and X2 are simultaneously fluoro; or X1 is deuterium and x2 is selected from hydrogen or deuterium;
each Y is independently selected from deuterium or hydrogen;
the hydrogen attached to the indole nitrogen is optionally replaced by deuterium;
each carbon is independently optionally replaced by 13C; and wherein at least hydrogen is replaced by deuterium or at least one carbon is replaced by 13C ; - b) subjecting said biological sample to a measuring device that distinguishes Compound 1 from said second compound;
- c) calibrating said measuring device to correlate the detected quantity of Compound 1 with the known concentration of said second compound added to said biological sample; and
- d) determining the concentration of said compound in said biological sample by comparing the detected quantity of Compound 1 with the detected quantity and known concentration of said second compound.
[0169] In one preferred embodiment, said second compound has the formula:
(TV), wherein:
Y is hydrogen or deuterium and;
each hydrogen atom is optionally substituted by deuterium and each carbon atom is optionally substituted by 13C .
[0170] Measuring devices that can distinguish Compound 1 from said second compound include any measuring device that can distinguish between two compounds that are of identical structure except that one contains one or more heavy atom isotope versus the other. Preferably, such a measuring device is a mass spectrometer.
[0171] In a preferred embodiment, at least three combined hydrogen atoms and carbons are, respectively, replaced by deuterium and 13C in said second compound; i.e. (total number of D) + (number of 13C) ≥3.
[0172] In another preferred embodiment, the method comprises the additional step of organically extracting both Compound 1 and said second compound from said biological sample prior to step b).
[0173] Compound 1 and the second compound will have similar solubility, extraction, and chromatographic properties, but significantly different molecular mass. Thus, the second compound is useful as an internal standard in a method that comprises the step of organic extraction to measure the efficiency of that extraction and to ensure an accurate determination of the true concentration of Compound 1 (see Tuchman M and McCann MT, Clin. Chem. 1999 45: 571; Leis HJ et. al., J. Mass Spectrom. 2001 36: 923; Taylor RL et. al. Clin. Chem. 2002 48: 1511).
[0174] The compounds of the present invention (the second compound) are particularly useful in this method since they are not radioactive and therefore do not pose a hazard to personnel handling the compounds. Thus, these methods do not require precautions beyond those normally applied in clinical sample analysis.
[0175] Furthermore, stably labeled isotopes have long been used to assist in research into the enzymatic mechanism of cytochrome P450 enzymes (Korzekwa KR et. al., Drug Metab. Rev. 1995 27: 45 and references therein; Kraus, JA and Guengerich, FP, J. Biol. Chem. 2005 280: 19496; Mitchell KH et. al., Proc. Natl. Acad. Sci. USA 2003 109: 3784).
[0176] In another embodiment, the invention provides a diagnostic kit comprising:
- a) a compound having the compound having the formula: II:
(II), wherein:X1 and X2 are simultaneously fluoro; or X1 is deuterium and X2 is selected from hydrogen or deuterium;
each Y is independently selected from deuterium or hydrogen;
the hydrogen attached to the indole nitrogen is optionally replaced by deuterium;
each carbon is independently optionally replaced by 13C ; and
at least hydrogen is replaced by deuterium or at least one carbon is replaced by 13C; and
- b) instructions for using said compound to determine the concentration of a test compound in a biological sample.
[0177] In a preferred embodiment, said compound has the formula:
(IV), wherein:
Y is hydrogen or deuterium and;
each hydrogen atom is optionally substituted by deuterium and each carbon atom is optionally substituted by 13C.
[0178] In another embodiment, the invention provides a method of evaluating the metabolic stability of a compound of formula II, comprising the steps of contacting the compound of formula II with a metabolizing enzyme source for a period of time; and comparing the amount of said compound to the metabolic products of said compound after said period of time.
[0179] In one preferred embodiment, the method comprises an additional step of comparing the amount of said compound to said metabolic products of said compound at an interval during said period of time. This method allows the determination of a rate of metabolism of said compound.
[0180] In another preferred embodiment, the method comprises the additional steps of contacting a compound of formula II with said metabolizing enzyme source; comparing the amount of said compound of formula II to the metabolic products of said compound of formula II after said period of time determining a rate of metabolism of said compound of formula I; and comparing the metabolic stability of Compound 1 to said compound of formula II. This method is useful in determining whether and at which sites on a compound of formula II additional deuterium or 13C substitution would cause increases in metabolic stability. It is also useful in comparing the metabolic stability of a compound of formula II with the metabolic stability of Compound 1.
[0181] A metabolizing enzyme source may be a purified, isolated or partially purified metabolic protein, such as a cytochrome P450; a biological fraction, such as a liver microsome fractions; or a piece of a metabolizing organ, such as a liver slice.
[0182] The determination of the amount of compound and its metabolic products is well known in the art. It is typically achieved by removing an aliquot from the reaction mixture and subjecting it to an analysis capable of distinguishing between the compound and its metabolites, such as reversed-phase HPLC with UV absorption or mass spectroscopic detection. Concentrations of both the metabolizing enzyme and the compound may be varied to determine kinetic parameters, for instance, by using appropriate nonlinear regression software such as is known in the art. By comparing the kinetic parameters of both a compound of formula n and Compound 1 an apparent steady-state deuterium isotope effect (D(V/K)) can be determined as the ratio of products formed in the hydrogen versus deuterium reactions.
[0183] The determination of a rate of metabolism of a compound of formula I may be achieved in a reaction separate from the reaction for determining the metabolism rate of Compound 1. Alternatively, Compound 1 may be admixed with a compound of formula I in a competition experiment to determine rates of disappearance of the two compounds, making use of analytical instrumentation capable of differentiating between the two compounds based on their mass differences.
[0184] In yet another embodiment, pre-steady state kinetics, such as V0, may be determined by means known in the art, for instance, using quench-flow apparatus, by monitoring the quenched reactions at varying times after mixing the compound or isotopologue with the metabolizing enzyme source.
[0185] In a related embodiment, the invention provides a kit comprising, in separate vessels: a) Compound 1; and b) a metabolizing enzyme source. The kit is useful for comparing the metabolic stability of a compound of formula II with Compound 1, as well as evaluating the effect of deuterium and 13C replacement at various positions on a compound of formula II. In a preferred embodiment, the kit further comprises instructions for using Compound 1 and said metabolizing enzyme source to evaluate the metabolic stability of a compound of formula II.
[0186] In order that the invention might be more fully understood, the following examples are set forth. They are not intended to limit the scope of the invention and further examples will be evident to those of ordinary skill in the art. In each example set forth herein, carbon shall be 12C, and hydrogen shall by 1H, each incorporated at its natural abundance, unless otherwise specified.
[0187] Example 1: 2,2-Difluorobenzo[d][1,3]dioxole-5-carbaldehyde. A solution of 127 mmol of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole in 200 mL of THF is cooled under argon in a CO2/acetone bath and treated with 1.05 equivalents ofn-BuLi in THF. The mixture is stirred for about 10 min in the cold, then treated with 1.2 equivalents ofDMF. The mixture is stirred for 30 min in the cold, then the cold bath is removed and the reaction is stirred for 1.5 h at ambient temperature and then quenched with 150 mL of saturated ammonium chloride solution. The organic layer is separated and the aqueous layer is washed 2x with ether. The combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (EtOAc/hexanes eluant) yields the title compound.
[0188] Example 2: 5-Bromo-6-deutero-2,2-difluorobenzo[d][1,3]dioxole. A solution of 24 mmol of 5,6-dibromo-2,2-diauorobenzo[d][1,3]dioxole (Chemos GmbH, Regenstauf, Germany) in 40 mL of THF is cooled under argon in a CO2/acetone bath and treated with 0.98 equivalents ofn-BuLi in THF. The mixture is stirred for about 10 min in the cold, then treated with 1 mL of D2O. The mixture is stirred for 15 min in the cold, then the cold bath is removed and stirring is continued for 1.5 h, then quenched with 40 mL of saturated ammonium chloride solution. The organic layer is then separated and the aqueous layer is washed 2x with ether. The combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (ether/hexanes eluant) yields the title compound.
[0189] Example 3:6-Deutero-2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde. A 13.2 mmol portion of the product of Example 2 is formylated using the general procedure described in example 1 yielding, after silica gel chromatography with EtOAc/hexanes eluant, the title product.
[0190] Example 4: 2,2-Difluorobenzo[d][1,3]dioxole-5-deuterocarbaldehyde. A 32.2 mmol sample of of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole is formylated using the general procedure described in example 1 except using N,N-dimethylfonnanlide-1-d as the formylating reagent to yield, after silica gel chromatography with EtOAc/hexanes eluant, the title product.
[0191] Example 5: (1R,3R)-Mefuyl 1-(2,2-difluorobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula IV, wherein E is methyl and each Y group is hydrogen). A solution of 37.4 mmol of D-tryptophun methyl ester and 41.1 mmol of the product of Example 1 in 220 mL of methylene chloride is cooled under argon in a -5 °C bath and treated with 5.4 mL of trifluoroacetic acid. The mixture is stirred for 30 min, the ice bath is removed, and stirring is continued for 17 h at room temperature. The reaction is again cooled in an ice bath and rendered slightly basic (pH ∼ 8.5-9) by portionwise addition of saturated NaHCO3 solution. After stirring an additional 45 min, the reaction is washed with 1 N NaHCO3 and the aqueous layer extracted twice with additional methylene chloride. The combined organic layers are washed with half-saturated brine, dried over MgSO4 and concentrated, yielding the title compound. Silica gel flash chromatography (CH3OH/CH2Cl2 eluent) yields the title product as the faster-moving product component while later fractions comprise the (1S,3R) stereoisomer.
[0192] Example 6: (1R,3R)-Methyl 2-(2-chloroacetyl)-1-(2,2-difluorobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula V, wherein E is methyl and each Y group is hydrogen). A 12.7 mmol portion of the product of example 5 in 80 mL of methylene chloride is treated with 15.2 mmol of sodium bicarbonate and cooled in an ice/water bath under an argon atmosphere. The mixture is stirred vigorously and treated dropwise with 30.7 mmol of chloroacetyl chloride. After stirring for 10 mm the ice bath is removed and stirring is continued for 1.5 h at room temperature. The mixture is partitioned between 150 mL each ether and saturated NaHCO3, and the organic layer is washed with water, then brine, and dried over MgSO4 and concentrated in vacuo. The resulting product is used in subsequent reactions without further purification.
[0193] Example 7: (6R,12aR)-6-(2,2-Difluorobenzo[d]l-1,3-dioxol-5-yl)-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-2-trideuteromethyl-1,4-dione (Formula III wherein Y9a, Y9b, and Y9c are deuterium and all other Y groups are hydrogen). A solution of 8.2 mmol of the product of example 6 in 30 mL of methanol is treated with 41 mmol of methylamine-d5 (Isotec) as an 18% solution in methanol. The mixture is heated at 50°C under argon for 17 h, then concentrated in vacuo. The residue is dissolved in methylene chloride and washed with water (2x) and half saturated brine, then dried over MgSO4 and concentrated in vacuo. Silica gel chromatography with methylene chloride/methanol as eluant yields the title product.
[0194] Example 8: (IR,3R)-Methyl 1-(6-deutero-2,2-difluorobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula IV, wherein E is methyl, Y4 is deuterium and all other Y groups are hydrogen). A sample of the product of Example 3 (6.6 mmol) is reacted with 38.5 mmol of D-tryptophan methyl ester using the general procedure described in example 5, yielding the mixed cis-trans product. Silica gel flash chromatography (CH3OH/CH2Cl2 eluent) of the product of example 8 gives the title product as the faster-moving product component.
[0195] Example 9: (6R,12aR)-6-(6-Deutero-2,2-difluorobenzo[d]-1,3-dioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (Formula in wherein Y4 is deuterium and all other Y groups are hydrogen). A portion of the product of example 8 (8.7 mmol) is reacted with methylamine (as a 33% (weight) solution in ethanol) using the general procedure described in example 6 yielding, after silica gel chromatography with methylene chloride/methanol as eluant, the title product.
[0196] Example 10: (1S,3R)-Methyl 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-deutero-2-propionyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (Formula IV, wherein E is methyl, Y7 is deuterium and all other Y groups are hydrogen). An 18.7 mmol sample of the product of Example 4 is subjected to Pictet-Spengler cyclization with 20.6 mmol of D-tryptophan methyl ester and 2.7 mL of CF3CO2D using the general procedure described in Example 5 yielding, after silica gel chromatography with methylene chloride/methanol as eluant, the title product as the faster-moving product component.
[0197] Example 11: (1R,3R)-Methyl 2-(2-chloroacetyl)-1-deutero-1-(2,2-difluorobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,b]lindole-3-carboxylate (Formula V, wherein E is methyl, Y7 is deuterium and all other Y groups are hydrogen). A 5.7 mmol portion of the product of Example 10 is chloracetylated according to the general procedure described in Example 6. The resulting product is used in subsequent reactions without further purification.
[0198] Example 12: (6R,12aR)-6-Deutero-6-(2,2-difluorobenzo[d]-1,3-dioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (Formula III wherein Y7 is deuterium and all other Y groups are hydrogen). A solution of 3.9 mmol of the product of Example 11 is reacted with methylamine using the general procedure described in Example 9 yielding, after silica gel chromatography with methylene chloride/methanol as eluant, the title product.
[0199] Example 13: (1R,3R)-Methyl 2-(2-dideuterochloroacetyl)-1-(2,2-difluorobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula V, wherein E is methyl, Y8a and Y8b are deuterium and all other Y groups are hydrogen). A solution of 6.8 mmol of chloroacetic acid-d3 (C/D/N Isotopes) and 7.2 mmol ofdiisopropylethylamine in 18 mL of methylene chloride is cooled in an ice/methanol bath under argon and treated dropwise with 6.8mmol of pivaloyl chloride. The solution is stirred for 20 min, then treated with a solution of 4.5 mmol of the product of example 5 and 4.5 mmol of diisopropylethylamine in 2 mL of methylene chloride. The solution is stirred for 16 h at 0 °C, then partitioned between 15 mL each of ether and saturated NaHCO3, and the organic layer is washed brine, dried over MgSO4 and concentrated in vacuo. The product is used for subsequent reactions without further purification.
[0200] Example 14: (6R,12aR)-3,3-Dideutero-6-(2,2-difluorobenzo[d]-1,3-dioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (Formula III wherein Y8a and Y8b are deuterium and all other Y groups are hydrogen).
The entire product of the product of Example 13, save a ∼2 mg retained portion, are reacted with methylamine using the general procedure described in Example 9 yielding, after silica gel chromatography with methylene chloride/methanol as eluant, the title product.
[0201] Example 15: (6R,12aR)-6-Deutero-6-(2,2-difluorobenzo[d]-1,3-dioxol-5-yl)-2-methyl-13C-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (Formula III wherein Y7 is deuterium and all other Y groups are hydrogen, and the N-methyl group is substituted with 13C). A heavy-walled pressure vial is charged with a 2.6 mmol portion of product of example 11 in 12 mL of methanol. The solution is treated with 5.2 mmol of methyl-13C-amine hydrochloride (Isotec) and 5.2 mmol of diisopropylethylamine. The vial is sealed and heated at 50 °C for 16 h, then the reaction is concentrated in vacuo, the residue partitioned between methylene chloride and water, and the organic layer washed with half saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography with methylene chloride/methanol as eluant yields the title compound.
[0202] Example 16: (1R,3R)-Methyl 2-(2-chloroacetyl-2-13C)-1-deutero-1-(2,2-difluorobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula V, wherein E is methyl, Y7 is deuterium and all other Y groups are hydrogen and the chloroacetyl methylene group is substituted with 13C). A 1.8 mmol portion of the product of Example 10 is chloroacetylated using the general procedure described in Example 13 except substituting chloroacetic acid-2-13C (Isotec) in place of chloroacetic acid-d3. Following workup, the product is used without subsequent purification.
[0203] Example 17: (6R,12aR)-6-Deutero-6-(2,2-difluorobenzo[d].1,3-dioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione-3-13C (Formula III wherein Y7 is deuterium and all other Y groups are hydrogen, and the unsubstituted methylene of the dioxopiperazine ring is substituted with 13C). The entire product of the product of Example 16, save a ∼2 mg retained portion, are reacted with methylamine using the general procedure described in Example 9 yielding, after silica gel chromatography with methylene chloride/methanol as eluant, the title product.
[0204] Example 18: (6R,12aR)-6-(2,2-Difluorobenzo[d]-1,3-dioxol-5-yl)-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-2-methyl-1,4-dione (Compound 2). A solution of 31.7 mmol of the product of example 6 in 100 mL of methanol is treated with 160 mmol of methylamine as a 33% solution in ethanol. The mixture is heated at 50°C under argon for 18 h, then concentrated in vacuo. The residue is dissolved in methylene chloride and washed with water (2x) and half saturated brine, then dried over MgSO4 and concentrated in vacuo. Silica gel chromatography with methylene chloride/methanol as eluant yields the title product.
[0205] Example 19: Deuterodibromomethane. A solution of 1.1 mole of sodium deuteroxide in 140 mL of deuterium oxide is treated under argon with 116 mmol of arsenious oxide to form a solution of sodium arsenite. Bromoform (190 mmol) is treated under argon with 6.5 mL of ethanol-d (CH3CH2OD) and 1 mL of the sodium arsenite solution and warmed briefly (heat gun) to initiate reaction. The remainder of the sodium arsenite solution is added via dropping funnel at a rate to maintain gentle reflux. Then the mixture is heated in a 100°C oil bath for an additional 4.5 h. The mixture is azeotropically distilled, then the distillate is separated and the aqueous layer extracted with 15 mL of pentane. The organic layers are combined, dried over CaCl2, and distilled to yield the title compound.
[0206] Example 20: 2-deuterobenzo[d][1,3]dioxole-5-carbaldehyde (Formula XII wherein X1 is D and X2 is H). A solution of 3,4-dihydroxybenzaldehyde (20 mmol) in 60 mL of dimethylformamide (DMF) is treated under argon with 60 mmol of the product of example 1 and 70 mmol of CsF. The mixture is heated in a 140 °C oil bath for 3 h with vigorous stirring. The mixture is then filtered, concentrated in vacuo, and the residue is purified by silica gel flash chromatography (ether/hexanes eluant), yielding the title product.
[0207] Example 21: 2,2-dideuterobenzo[d][1,3]dioxole-5-carbaldehyde (Formula XII wherein X1 is D and X2 is H). A solution of A solution of 3,4-dihydroxybenzaldehyde (150 mmol) in 110 mL of dimethylformamide (DMF) is treated under argon with 600 mmol of dideuterodichloromethane (Aldrich Chemicals) and 720 mmol of CsF. The mixture is heated under reflux for 3 h with vigorous stirring. The mixture is then filtered, concentrated in vacuo, and the residue is purified by silica gel flash chromatography (ether/hexanes eluant), yielding the title product.
[0208] Example 22: (1R,3R)-Methyl 1-(2-deuterobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido(3,4,-b]indole-3-carboxylate (Formula XIII, wherein X1 is D, X2 is H, and E is methyl). A solution of 12.7 mmol of D-tryptophan methyl ester and 13.9 mmol of the product of Example 21 in 80 mL of methylene chloride is cooled under argon in a -5 °C bath and treated with 1.9 mL of deuterotrifluoroacetic acid (CF3CO2D). The mixture is stirred for 30 min, the ice bath is removed, and stirring is continued for 21 h at room temperature. The reaction is again cooled in an ice bath and rendered slightly basic (pH∼8.5-9) by portionwise addition of saturated NaHCO3 solution. After stirring an additional 45 min, the reaction is washed with 1 N NaHCO3 and the aqueous layer extracted twice with additional methylene chloride. The combined organic layers are washed with half-saturated brine, dried over MgSO4 and concentrated, yielding the title compound. Silica gel flash chromatography (CH3OH/CH2Cl2 eluent) yields the title product as the faster-moving product component while later fractions comprise the (1S,3R) stereoisomer.
[0209] Example 23: (1R,3R)-Methyl 2-(2-chloroacetyl)-1-(2-deuterobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula XIV wherein X1 is D, X2 is H, and E is methyl). A 4.1 mmol portion of the product of Example 22 in 30 mL of methylene chloride is treated with 5.0 mmol of sodium bicarbonate and cooled in an ice/water bath under an argon atmosphere. The mixture is stirred vigorously and treated dropwise with 9.9 mmol of chloroacetyl chloride. After stirring for 10 min the ice bath is removed and stirring is continued for 1.5 h at room temperature. The mixture is partitioned between 60 mL each ether and saturated NaHCO3, and the organic layer is washed with water, then brine, and dried over MgSO4 and concentrated in vacuo. Crystallization from ether/hexanes yields the title product.
[0210] Example 24: (6R,12aR)-6-(2-deuterobenzo[d]-1,3-dioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (Formula IV wherein Y = H). A solution of 1.8 mmol of the product of Example 23 in 30 mL of methanol is treated with 9 mmol of methylamine (as a 33% (weight) solution in ethanol). The mixture is heated at 50 °C under argon for 17 h, then concentrated in vacuo. The residue is dissolved in methylene chloride and washed with water (2x) and half saturated brine, then dried over MgSO4 and concentrated in vacuo. Recrystallization from 2-propanol yields the title compound.
[0211] Example 25: (1R,3R)-Methyl 1-(2,2-dideuterobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula XIII, wherein X1 is D, X2 is H, and E is methyl). A sample of the product of Example 21 (42.2 mmol) is reacted with 38.5 mmol of D-tryptophan methyl ester using the general procedure described in Example 22, yielding the mixed cis-trans product. Silica gel flash chromatography (CH3OH/CH2Cl2 eluent) of the product of example 8 gives the title product as the faster-moving product component.
[0212] Example 26: (1R,3R)-Methyl 2-(2-chloroacetyl)-1-(2,2-dideuterobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate (Formula XIV wherein X1 is D and X2 is H, and E is methyl). A 14.1 mmol portion of the product of Example 25 is reacted with chloroacetyl choride using the general procedure described in Example 23 yielding, after crystallization from ether/hexanes, the title product.
[0213] Example 27: (6R,12aR)-6-(2,2-dideuterobenzo[d]-1,3-dioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (Formula IV wherein Y = D). A portion of the product of Example 26 (8.7 mmol) is reacted with alcoholic methylamine using the general procedure described in Example 23 yielding, after crystallization from 2-propanol, the title product.
[0214] Example 28: (1R,3R)-Methyl 2-(2-chloroacety1-2-13C)-1-(2,2-dideuterobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate. A solution of 2.3 mmol of chloroacetic acid-2-13C (Isotec) and 2.3 mmol of diisopropylethylamine in 4 mmol of methylene chloride is cooled in an ice/methanol bath under argon and treated dropwise with 2.2 mmol of pivaloyl chloride. The solution is stirred for 20 min, then treated with a solution of 2.2 mmol of the product of Example 25 and 2.2 mmol of diisopropylethylamine in 1 mL of methylene chloride. The solution is stirred for 16 h at 0 °C, then partitioned between 15 S mL each of ether and saturated NaHCO3 and the organic layer is washed brine, dried over MgSO4 and concentrated in vacuo. Crystallization from ether/hexanes yields the title product.
[0215] Example 29: (6R,12aR)-6-(2,2-dideuterobenzo[d]-1,3-dioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indolc-1,4-dione-3-13C. A solution of 0.6 mmol of the product of Example 28 is reacted with methylamine using the general procedure described in Example 24 yielding, after crystallization from 2-propanol, the title product.
[0216] Example 30: (6R,12aR)-6-(2,2-dideuterobenzo[d]-1,3-dioxol-5-yl)-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-2-tndeuteromethyl-1,4-dione. A 1.8 mmol sample of the product of Example 26 is reacted with methylamine-d5 (Isotec) as an 18% solution in methanol using the general procedure described in Example 24, modified by using 3 equivalents of the amine and carrying out the reaction in a sealed pressure vial. Workup and crystallization from 2-propanol yields the title compound.
Example 31: (6R,12aR)-6-(2,2-dideuterobenzo[d]-1,3-dioxol-5-yl)-2-methyl-13C 1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione. A heavy-walled pressure vial is charged with a 0.96 mmol portion of product of Example 26 in 8 mL of methanol. The solution is treated with 1.9 mmol of methyl-13C-amine hydrochloride (Isotec) and 1.9 mmol of diisopropylethylamine. The vial is sealed and heated at 50 °C for 17 h, then the reaction is concentrated in vacuo, the residue partitioned between methylene chloride and water, and the organic layer washed with half saturated brine, dried over MgSO4, and concentrated in vacuo. Crystallization from 2-propanol yields the title compound.
[0217] Example 32: 6R,12aR)-6-(2,2-dideuterobenzo[d]-1,3-dioxol-5-yl)- 2-methyl-13C-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione-3-13C. A 0.6 mmol portion of the product of example 10 is reacted with methyl-13C-amine hydrochloride using the general procedure described in Example 31 to yield the title product.
[0218] Example 33: Inhibition of PDE5 and subtype selectivity. Activity of test compounds in PDE5 human isoform inhibition is conducted by MDS Pharma Services using essentially the protocol of Hidaka H and Asano T, Biochim. Biophys. Acta 1976 429: 485. Counterscreens using PDE1 and PDE6 are also carried out by MDS Pharma Services. These tests demonstrate nanomolar activity of each tested compound of formula II.
[0219] Example 20: Hypotensive effects in the spontaneous hypertensive rat model. Effects of the products of examples 7, 9, 12, 18, 27 and 30 are tested by oral administration to spontaneously hypertensive rats at Cerep, using essentially the procedure of Bazil MK et. al., J. Cardiovasc. Pharmacol 1993 22: 897 and a sample size of 8 rats per group. Each compound demonstrates significant reductions in blood pressure sustained over 8 h when dosed at 10 mg/kg.
[0220] All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, technical data sheets, internet web sites, databases, patents, patent applications, and patent publications.
[0221] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
[0222] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following embodiments and claims.
Embodiments
[0223]
- 1. An isolated compound of Formula II:
(II), or a prodrug or a prodrug salt thereof; or a hydrate or a solvate or a polymorph of any of the foregoing; wherein:X1 and X2 are simultaneously fluoro; or X1 is deuterium and X2 is selected from hydrogen or deuterium;
each Y is independently selected from deuterium or hydrogen;
the hydrogen attached to the indole nitrogen is optionally replaced by deuterium; and
each carbon is independently optionally replaced by 13C.
- 2. The compound or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to embodiment 1, wherein at least one Y is deuterium.
- 3. The compound or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to embodiment 2, wherein at least one of Y4, Y7 Y8a, Y8b, Y9a, Y9b, or Y9c are deuterium.
- 4. The compound or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph
of any of the foregoing according to embodiment 3, wherein said compound is deuterated
at one or more of:
- a. Y4;
- b. Y7:
- c. Y8a and Y8b simultaneous; or
- d. Y9a, Y9b and, Y9e simultaneously.
- 5. The compound or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments 1 to 4, wherein X1 and X2 are simultaneously fluoro.
- 6. The compound, prodrug or prodrug salt thereof; or hydrate or solvate or polymorph
of any of the foregoing according to embodiment 5, having a formula:
wherein the hydrogen attached to the indole nitrogen is not replaced by deuterium and wherein no carbon atoms are replaced by 13C. - 7. The compound or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments 1 to 4, wherein X1 is deuterium, and X2 is selected from hydrogen or deuterium.
- 8. The compound or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments 1 to 4, wherein X1 and X2 are simultaneously deuterium.
- 9. The compound or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to embodiment 8, wherein at least three Y are deuterium.
- 10. The compound or prodrug or prodrug salt or hydrate or solvate or polymorph of any of the foregoing according to embodiment 8 or 9, wherein one carbon atom is replaced by 13C.
- 11. The compound according to any one of embodiments 1 to 4, or 5 to 10. wherein all hydrogen atoms not replaced by deuterium and all carbon atoms not replaced by 13C are present at their natural isotopic abundance.
- 12. A mixture consisting essentially of:
- a. a compound according to any one of embodiments 1 to 10, wherein said compound comprises at least one deuterium atom or at least one 13C atom; and
- b. lighter isotopologues of said compound,
wherein at least 50% of said mixture is said compound.
- 13. A mixture consisting essentially of:
- a. a compound according to any one of embodiments 1 to 10, wherein said compound comprises at least one deuterium atom or at least one 13C atom; and
- b. lighter isotopologues of said compound,
wherein at least 50% of the compounds in said mixture comprise an isotope at each position occupied by an isotope in the compound.
- 14. A composition comprising an effective amount of a compound, or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments 1 to 10; and an acceptable carrier.
- 15. The composition according to embodiment 14, wherein said composition is formulated for pharmaceutical use, and wherein the carrier is a pharmaceutically acceptable carrier.
- 16. The composition according to embodiment 15, further comprising an effective amount of a second therapeutic agent, wherein said second therapeutic agent is useful alone or in combination with a compound of formula for treating or preventing a condition selected from stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, thrombocythemia, an inflammatory disease, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, a gut motility disorder, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, irritable bowel syndrome , human female sexual dysfunction, a recurrent human sexual deficiency condition, a sexual deficiency state in a human due to a co-existing condition of epilepsy, craniopharyngioma, or hypogonadism, a sexual deficiency state in a human due to hysterectomyoophorectomy, hysterectomy or oophorectomy, other sexual deficiency states in a human; hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridemia, diabetes, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, vascular restenosis, endothelial dysfunction, depression, epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, , anxiety, panic, pain, including visceral and pelvic pain and pain associated with dysmenorrhea; sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, cystitis, pancreatitis, cyclical oedema, Menires disease, hyperaldosteroneism (primary and secondary); hypercalciuria and lower urinary tract symptoms, other than urinary incontinence, associated with overactive bladder and/or benign prostatic hyperplasia; or impaired mating in a non-human mammal.
- 17. The composition according to embodiment 16, wherein said additional therapeutic agent is selected from one or more of a vasodilator, prostaglandin E1, prostacyclin, an α-adrenergic blocker, a mixed α,β-adrenergic blocker, an α2-adrenergic blockers, an ACE inhibitor, an NEP inhibitor, a centrally acting dopaminergic agent, a vasoactive intestinal peptide a calcium channel blocker, a thiazide; (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1ij]quinolin-2(1 1H)-one. (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4.5,1-ij]quinoline-2(1H)- thione, and pharmaceutically acceptable salts thereof; a 5-HT2 receptor ligand, in particular, 5-HT2a and 5-HT2c receptor ligands; an acetylcholine esterase antagonist, a vasopressin receptor family antagonist, or a pharmaceutically acceptable derivative thereof, I-deprenyl or propargylamine compounds, human melanocortin-4 receptor (MC-4R) agonists, gamma-butyrobetaine, an alpha-2-delta ligand, an angiotensin 11 receptor antagonist, a prostaglandin E2 receptor subtype EP1 antagonist, an endothelin antagonist, an antidiabetic agent, an HMO-Co-a reductase inhibitor, a serotonin reuptake inhibitor (SSRI), or a pharmaceutically acceptable salt thereof.
- 18. An article of manufacture comprising separate dosage forms of a compound, or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments 1 to 10; and an additional therapeutic agent, wherein both dosage forms are in a single container.
- 19. The use of a compound, or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments 1 to 10 for the manufacture of a medicament for inhibiting PDE5 activity.
- 20. The use of a compound, or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments 1 to 10 for the manufacture of a medicament for increasing cGMP levels in arterial wall tissue or in corpus cavernosal smooth muscle.
- 21. The use of a compound, or prodrug or prodrug salt thereof; or hydrate or solvate or polymorph of any of the foregoing according to any one of embodiments I to 10 for the manufacture of a medicament useful to treat a subject suffering from or susceptible to erectile dysfunction; stable, unstable and variant angina; hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular diseases, vascular disorders, thrombocythemia, inflammatory diseases, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, gut motility disorders, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, irritable bowel syndrome, erectile dysfunction in animals, female arousal disorder in females; low sperm count, for the purpose of promoting fertilization of an ovum; reducing insulin resistance, stimulating ovarian follicular growth, preventing or treating a condition involving fibrosis, and for alleviating pain or spasticity in a patient suffering from spinal cord injury, said method comprising the step of administering to said subject a composition comprising an effective amount of a compound of formula II; or a prodrug or a prodrug salt thereof; or a hydrate, solvate or polymorph of any of the foregoing; and an acceptable carrier.
- 22. The use according to embodiment 20, wherein the medicament is useful to alleviate or prevent erectile dysfunction.
- 23. The use according to embodiment 22, wherein the intended recipient of the medicament is a human male.
- 24. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent female arousal disorder.
- 25. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent congestive heart failure.
- 26. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent hypertension.
- 27. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent angina.
- 28. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent renal failure.
- 29. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent vascular disorders.
- 30. The use according to embodiment 21, wherein the medicament is useful to alleviate postpercutaneous transluminal coronary or carotid angioplasty.
- 31. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent benign prostatic hypertrophy.
- 32. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent preterm labor.
- 33. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent and irritable bowel syndrome.
- 34. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent atherosclerosis.
- 35. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent myocardial infarction.
- 36. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent asthma.
- 37. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent stroke.
- 38. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent inflammatory diseases.
- 39. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent thrombocythemia.
- 40. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent pheochromocytoma.
- 41. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent osteoporosis.
- 42. The use according to embodiment 21, wherein the medicament is useful to enhance mating in animals.
- 43. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent insulin resistance.
- 44. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent a condition involving fibrosis.
- 45. The use according to embodiment 21, wherein the medicament is useful to alleviate or prevent pain or spasticity in a patient suffering from spinal cord injury.
- 46. The use according to embodiment 21, wherein said medicament is intended to be administered with a second therapeutic agent, wherein said second therapeutic agent is conventionally used alone, or is effective in combination with a compound of formula For treating or preventing a condition selected from stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, thrombocythemia, an inflammatory disease, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, a gut motility disorder, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, irritable bowel syndrome , human female sexual dysfunction, a recurrent human sexual deficiency condition, a sexual deficiency state in a human due to a co-existing condition of epilepsy, craniopharyngioma, or hypogonadism, a sexual deficiency state in a human due to hysterectomyoophorectomy, hysterectomy or oophorectomy, other sexual deficiency states in a human; hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridemia, diabetes, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, vascular restenosis, endothelial dysfunction, depression, epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, anxiety, panic, pain, including visceral and pelvic pain and pain associated with dysmenorrhea; sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, cystitis, pancreatitis, cyclical oedema, Menires disease, hyperaldosteroneism (primary and secondary); hypercalciuria and lower urinary tract symptoms, other than urinary incontinence, associated with overactive bladder and/or benign prostatic hyperplasia; or impaired mating in a non-human mammal, wherein said second therapeutic agent is administered to said patient as part of said composition or as a separate dosage form.
- 47. The use according to embodiment 46, wherein said additional therapeutic agent is selected from one or more of a vasodilator, prostaglandin E1, prostacyclin, an α-adrenergic blocker, a mixed α,β-blocker, an α2-adrenergic blocker, an ACE inhibitor, an NEP inhibitor, a centrally acting dopaminergic agent, a vasoactive intestinal peptide, a calcium channel blocker, a thiazide; (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one, (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione and pharmaceutically acceptable salts thereof a 5-HT2 receptor ligand, in particular, 5-HT2a and 5-HT2c receptor ligands; an acetylcholine esterase antagonist; a vasopressin receptor family antagonist, or a pharmaceutically acceptable derivative thereof; 1-deprenyl or propargylamine compounds; human melanocortin-4 receptor (MC-4R) agonists, gamma-butyrobetaine, an alpha-2-delta ligand, an angiotensin II receptor antagonist, a prostaglandin E2 receptor subtype EP1 antagonist, an endothelin antagonist, an antidiabetic agent, an HMG-Co-a reductase inhibitor; a serotonin reuptake inhibitor (SSR1), or a pharmaceutically acceptable salt thereof.
- 48. A compound of formula XIIIa
(XIIIa), wherein:D is deuterium;
Y is selected from hydrogen or deuterium;
each carbon atom is optionally replaced by 13C; and
each hydrogen atom is optionally replaced by deuterium.
- 49. The compound according to embodiment 48, wherein Y is deuterium.
- 50. The compound according to embodiment: 49, wherein all hydrogen atoms and all carbon atoms, are present at their natural isotopic abundance.
- 51. A compound of formula
(XIV), wherein:X1 and X2 are simultaneously fluoro; or X1 is deuterium and X2 is selected from hydrogen or deuterium;
Y is selected from hydrogen or deuterium;
E is an ester group labile to ring closure during cyclic amide formation; each carbon atom is optionally 13C; and
each hydrogen is optionally replaced by deuterium.
- 52. The compound according to embodiment 5 1, wherein E is methyl, ethyl, benzyl, or allyl.
- 53. The compound according to embodiment 51 or 52, wherein at least one Y is deuterium.
- 54. The compound according to embodiment 53, wherein Y4 is deuterium.
- 55. The compound according to embodiment 53, wherein Y7 is deuterium.
- 56. The compound according to embodiment 53, wherein at least one of Y8a and Y8b is independently deuterium.
- 57. The compound according to embodiment 56, wherein both of Y8aand Y8b are independently deuterium.
- 58. The compound according to embodiment 53, wherein to 3 hydrogen atoms are replaced by deuterium.
- 59. The compound accord ing to embodiment 58, wherein 1 carbon atom is 13C.
- 60. The compound according to any one of embodiments 51 to 59, wherein all hydrogen atoms not substituted by deuterium and all carbon atoms not substituted by 13C are present at their natural isotopic abundance.
- 61. The compound according to any one of embodiments 51 to 60, wherein X1 and X2 are simultaneously fluoro.
- 62. The compound according to any one of embodiments 51 to 60, wherein X1 is deuterium and X2 is selected from hydrogen or deuterium.
- 63. The compound according to embodiment 62, wherein X2 is deuterium.
- 64. A compound of formula XV:
(XV), wherein:X1 and X2 are simultaneously fluoro; or X1 is deuterium and X2 is selected from hydrogen or deuterium;
Z is leaving group;
each Y is independently selected from hydrogen or deuterium;
E is an ester group labile to ring closure during cyclic amide formation;
the hydrogen attached to each nitrogen is optionally replaced by deuterium; and each carbon atom is optionally replaced by 13C.
- 65. The compound according to embodiment 64, wherein Z is chloride, bromide, iodide, mesylate, or tosylate,
- 66. The compound according to embodiment 64, wherein E is methyl, ethyl, benzyl, or allyl.
- 67. The compound according to embodiment 64, wherein X is chloride, bromide, iodide, mesylate, or tosylate; and E is methyl, ethyl, benzyl, or allyl.
- 68. The compound according to any one of embodiments 64 to 67, wherein at least one Y is deuterium.
- 69. The compound according to embodiment 68, wherein Y4 is deuterium.
- 70. The compound according to embodiment 68, wherein Y7 is deuterium.
- 71. The compound according to embodiment 68, wherein at least one of Y8a and Y8b is independently deuterium.
- 72. The compound according to embodiment 71, wherein both of Y8a and Y8b are independently deuterium.
- 73. The compound according to embodiment 68, wherein I to 3 hydrogen atoms are replaced by deuterium.
- 74. The compound according to embodiment 73, wherein 1 carbon atom is 13C
- 75. The compound according to any one of embodiments 64 to 74, wherein all hydrogen atoms not substituted by deuterium and all carbon atoms not substituted by 13C are present at their natural isotopic abundance.
- 76. The compound according to any one of embodiments 64 to 75, wherein X1 and X2 are simultaneously fluoro.
- 77. The compound according to any one of embodiments 64 to 75, wherein X1 is deuterium and X2 is selected from hydrogen or deuterium.
- 78. The compound according to embodiment 77, wherein X2 is deuterium.
- 79. A method of determining the concentration of Compound 1 in a biological sample
comprising the steps of:
- a. adding a known concentration of a compound according to any one of embodiments 1 to 10 to a biological sample;
- b. subjecting said biological sample to a measuring device that distinguishes Compound from said compound;
- c. calibrating said measuring device to correlate the detected quantity of said compound with the known concentration of said compound added to said biological sample; and
- d. determining the concentration of Compound 1 in said biological sample by comparing the detected quantity of Compound with the detected quantity and known concentration of said compound.
- 80. The method according to embodiment 79, wherein said compound comprises at least 3 heavy atom isotopes independently selected from deuterium or 13C.
- 81. The method according to embodiment 79, comprising the additional step of organically extracting Compound 1 and said compound from said biological sample prior to step b.
- 82. A diagnostic kit comprising a compound according to any one of embodiments 1 to 10 in a sealed vessel; and instructions for using said compound to determine the concentration of Compound 1 in a biological sample.
- 83. The kit according to embodiment 82, wherein the compound of formula I comprises at least 3 heavy atom isotopes independently selected from deuterium or 13C.
- 84. A method of evaluating the metabolic stability of a compound according to any
one of embodiments 1 to 10, comprising the steps of:
e. contacting the compound with a metabolizing enzyme source for a period of time; and
f. comparing the amount of said compound to metabolic products of said compound after said period of time.
- 85. The method according to embodiment 84, wherein the method comprises an additional step of comparing the amount of said compound to said metabolic products of said compound at an interval during said period of time.
- 86. The method according to embodiment 84, wherein the method comprises the additional steps of: c) contacting an isotopologue of said compound with said metabolizing enzyme source; d) comparing the amount of said isotopologue to metabolic products of said isotopologue after said period of time; and e) comparing the metabolic stability of said compound to said isotopologue, wherein steps c and d are performed before, simultaneously with in a different reaction vessel from, simultaneously within the same reaction vessel as, or after, steps a and b.
- 87. The method according to embodiment 86, wherein said isotopologue is Compound 1.
- 88. A diagnostic kit comprising, in separate vessels, Compound 1 and a metabolizing enzyme source.
- 89. The diagnostic kit according to embodiment 82, further comprising instructions for using said kit to compare the metabolic stability of one or more compounds according to any one of embodiments 1 to 10 with the metabolic stability of Compound 1.
1. An isolated compound of Formula II:
or a pharmaceutically acceptable salt thereof; wherein:
or a pharmaceutically acceptable salt thereof; wherein:
X1 is deuterium and X2 is selected from hydrogen and deuterium;
each of Y3, Y4, Y6, Y7 Y8a,Y8b, Y9a, Y9b, Y9c, Y10, Y11a, Y11b, Y13 Y14, Y15, and Y16 is independently selected from deuterium or hydrogen; and
the hydrogen attached to the indole nitrogen is optionally replaced by deuterium.
2. The compound according to claim 1, wherein at least one Y is deuterium.
3. The compound according to claim 2, wherein said compound is deuterated at one or more
of:
a. Y4;
b. Y7;
c. Y8a and Y8b simultaneously; or
d. Y9a, Y9b and, Y9c simultaneously.
4. The compound according to any one of claims 1 to 3, wherein X1 and X2 are simultaneously deuterium.
5. The compound according to claim 4, wherein at least three Y are deuterium.
6. The compound according to any one of claims 1 to 5, wherein all hydrogen atoms not
replaced by deuterium and all carbon atoms not replace by 13C are present at their natural isotopic abundance.
7. A composition comprising an effective amount of a compound according to any one of
claims 1 to 6 and an acceptable carrier.
8. The composition according to claim 7, wherein said composition is formulated for pharmaceutical
use, and wherein the carrier is a pharmaceutically acceptable carrier.
9. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable
salt thereof for use in inhibiting PDE5 activity in a subject.
10. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable
salt thereof for use in increasing cGMP levels in arterial wall tissue or in corpus
cavernosal smooth muscle in a subject.
11. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable
salt thereof for use in treating a subject suffering from or susceptible to erectile
dysfunction; stable, unstable and variant angina; hypertension, pulmonary hypertension,
chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant
hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic
renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral
vascular diseases, vascular disorders, thrombocythemia, inflammatory diseases, myocardial
infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis,
glaucoma, peptic ulcer, gut motility disorders, postpercutaneous transluminal coronary
or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm
labor, benign prostatic hypertrophy, irritable bowel syndrome, erectile dysfunction
in animals, female arousal disorder in low sperm count, for the purpose or promoting
fertilization of an ovum; reducing insulin resistance, stimulating ovarian follicular
growth, preventing or treating a condition involving fibrosis, and for alleviating
pain or spasticity in a patient suffering from spinal cord injury.
12. The compound for use according to claim 11, for alleviating or preventing erectile
dysfunction.
13. The compound for use according to claim 11, for alleviating or preventing hypertension.
14. The compound for use according to claim 11, for alleviating or preventing vascular
disorders.
15. The compound for use according to claim 11, for alleviating or preventing benign prostatic
hypertrophy.
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